Glycopeptide derivatives and pharmaceutical compositions containing the same

ABSTRACT

Disclosed are derivatives of glycopeptide compounds having at least one substituent of the formula:
 
—R a —Y—R b —(Z) x 
 
where R a , R b , Y, Z and x are as defined, and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 09/470,209, filedDec. 22, 1999, now U.S. Pat. No. 6,392,012 which application claims thebenefit of U.S. Ser. No. 60/113,728, filed December 23, 1998; U.S. Ser.No. 60/129,313, filed Apr. 14, 1999; U.S. Ser. No. 60/164,024, filedNov. 4, 1999; and U.S. Ser. No. 60/169,978, filed Dec. 10, 1999; thedisclosures of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel derivatives of glycopeptide antibiotics.This invention also relates to pharmaceutical compositions containingsuch glycopeptide derivatives, to methods of using such glycopeptidederivatives as antibacterial agents, and to processes for preparing suchglycopeptide derivatives.

2. Background

Glycopeptides are a well-known class of antibiotics produced by variousmicroorganisms. These complex multi-ring peptide compounds are effectiveantibacterial agents against a majority of Gram-positive bacteria. Theuse of glycopeptides as antibiotics, however, has been overshadowed bythe semi-synthetic penicillins, cephalosporins and lincomycin due to thehigher levels of mammalian toxicity observed with the glycopeptides. Inrecent years, however, bacteria resistant to the penicillins,cephalosporins and the like have emerged resulting in, for example,multiple-resistant and methicillin-resistant staphylococcal (MRS)infections. Glycopeptides, such as vancomycin, are typically effectiveagainst such microorganisms and vancomycin has become the drug of lastresort for MRS and other infections. The glycopeptides are believed tobe effective against such resistant microorganism because they have adifferent mode of action than other antibiotics. In this regard, theglycopeptides are believed to selectively inhibit a different step inbacterial cell wall synthesis than the penicillin-type antibiotics.

More specifically, the cell wall of bacteria consists of linearpolysaccharide chains cross-linked by short peptides. This arrangementof cross-linked polysaccharides confers mechanical support to the cellwall, thus preventing the bacteria from bursting due to its highinternal osmotic pressure. During the synthesis of the bacterial cellwall, cross-linking of the polysaccharides takes place afterlipid-linked disaccharide-pentapeptide constructs are incorporated intolinear polysaccharide chains by a transglycolase enzyme. The subsequentcross-linking reaction is the last step in the synthesis of the cellwall and is catalyzed by an enzyme known as peptidoglycantranspeptidase.

One method by which antibacterial agents exert their antibacterialactivity is by inhibiting the transglycosylase enzyme, thus interferingwith the penultimate step in the synthesis of the bacterial cell wall.Although not wishing to be bound by theory, it is believed thatglycopeptide antibiotics, such as vancomycin, bind with high affinityand specificity to N-terminal sequences (i.e.,L-lysyl-D-alanyl-D-alanine in vancomycin-sensitive organisms) of thepeptidoglycan precursors (known as lipid intermediate II). By binding toand sequestering these precursors, vancomycin prevents their utilizationin cell wall biosynthesis. Thus, vancomycin inhibits the bacterialtransglycosylase that is responsible for adding lipid intermediate IIsubunits to growing peptidoglycan chains. This step of bacterial cellwall synthesis preceeds the cross-linking transpeptidation step which isknown to be inhibited by beta-lactams antibiotics. It is also believedthat vancomycin inhibits transpeptidation which involves theD-alanyl-D-alanine termini. However, since this step occurs subsequentto transglycosylation, inhibition of transpeptidation is not directlyobserved.

A number of derivatives of vancomycin and other glycopeptides are knownin the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987;4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Otherderivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353;WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer.Chem. Soc., 1996, 118, 13107-13108; J. Amer. Chem. Soc., 1997, 119,12041-12047; and J. Amer. Chem. Soc., 1994, 116, 4573-4590. Thedisclosures of these and other documents referred to throughout thisapplication are incorporated herein by reference in their entirety.

A need exists, however, for glycopeptide derivatives having improvedactivity, selectivity and reduced mammalian toxicity. Moreover, certainmicroorganisms are beginning to develop resistance to vancomycin, suchas vancomycin-resistant enterococci (VRE). Accordingly, it would behighly desirable to provide novel glycopeptide derivatives which areeffective against a broad spectrum of bacteria, including resistantstrains such as VRE. Moreover, it would be highly advantageous toprovide glycopeptide derivatives having improved antibacterial activityand selectivity, and low mammalian toxicity.

SUMMARY OF THE INVENTION

The present invention provides novel derivatives of glycopeptideantibiotics having improved properties compared to the unsubstitutedglycopeptide, including enhanced activity, selectivity and reducedmammalian toxicity. For example, certain vancomycin derivatives of thisinvention demonstrate greatly enhanced antibacterial activity comparedto vancomycin itself. Such vancomycin derivatives are also highlyeffective against vancomycin-resistant enterococci strains whileexhibiting reduced mammalian toxicity.

Accordingly, in one of its composition aspects, this invention providesa glycopeptide compound having at least one substituent of the formula:—R^(a)—Y—R^(b)—(Z)_(x)

wherein

each R^(a) is independently selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,alkynylene and substituted alkynylene;

each R^(b) is independently selected from the group consisting of acovalent bond, alkylene, substituted alkylene, alkenylene, substitutedalkenylene, alkynylene and substituted alkynylene, provided R^(b) is nota covalent bond when Z is hydrogen;

each Y is independently selected from the group consisting of oxygen,sulfur, —S—S—, —NR^(c)—, —S(O)—, —SO₂—, —NR^(c)C(O)—, —OC(O)—,—NR^(c)SO₂—, —OSO₂—, —C(O)NR^(c)—,—C(O)O—, —SO₂NR^(c)—,—SO₂O—,—P(O)(OR^(c))O—, —P(O)(OR^(c))NR^(c)—, —OP(O)(OR^(c))O—,—OP(O)(OR^(c))NR^(c)—, —OC(O)O—, —NR^(c)C(O)O—, —NR^(c)C(O)NR^(c)—,—OC(O)NR^(c)— and —NR^(c)SO₂NR^(c)—;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

each R^(c) is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclicand —C(O)R^(d);

each R^(d) is independently selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

x is 1 or 2;

and pharmaceutically acceptable salts thereof;

provided that:

(i) when Y is —NR^(c)—, R^(c) is alkyl of 1 to 4 carbon atoms, Z ishydrogen and R^(b) is alkylene, then R^(b) contains at least 5 carbonatoms;

(ii) when Y is —C(O)NR^(c)—, Z is hydrogen and R^(b) is alkylene, thenR^(b) contains at least 5 carbon atoms;

(iii) when Y is sulfur, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 7 carbon atoms; and

(iv) when Y is oxygen, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 11 carbon atoms.

Preferably, the glycopeptide compound is substituted with from 1 to 3substituents of the formula —R^(a)—Y—R^(b)—(Z)_(x).

Each R^(a) is preferably independently selected from alkylene havingfrom 1 to 10 carbon atoms, more preferably, from 1 to 6 carbon atoms. Ina preferred embodiment, R^(a) is ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—) or butylene (—CH₂CH₂CH₂CH₂—). Still more preferably, R^(a)is ethylene or propylene.

When Z is hydrogen, R^(b) is preferably alkylene of from 8 to 12 carbonatoms. Accordingly, in this embodiment, R^(b) and Z preferably form ann-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl group. When Z is otherthan hydrogen, R^(b) is preferably a covalent bond or alkylene of from 1to 10 carbon atoms. In this embodiment, R^(b) is preferably, a covalentbond, methylene, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —(CH₂)₉— or —(CH₂)₁₀—.

Each Y is preferably independently selected from the group consisting ofoxygen, sulfur, —S—S—, —NR^(c)—, —S(O)—, —SO₂—, —NR^(c)C(O)—, —OC(O)—,—NR^(c)SO₂—, —C(O)NR^(c)—, —C(O)O— and —SO₂NR^(c)—. More preferably, Yis oxygen, sulfur, —NR^(c)— or —NR^(c)SO₂—.

Preferably, each Z is independently selected from hydrogen, aryl,cycloalkyl, heteroaryl and heterocyclic. More preferably, Z is hydrogenor aryl. When Z is aryl, preferred Z group include phenyl, substitutedphenyl, biphenyl, substituted biphenyl and terphenyl groups.Particularly preferred Z groups are phenyl, 4-isobutylphenyl,4′-chlorobiphenyl-4-yl, 4′-trifluoromethylbiphenyl-4-yl, 4 (naphth 2yl)phenyl, 4-(2-phenylethynyl)phenyl, 4-(3,4-dichlorobenzyloxy) phenyl,and p-terphenyl.

Preferably, x is 1.

Particularly preferred —R^(a)—Y—R^(b)—(Z)_(x) groups of this inventionare selected from the group consisting of:

-   -   —CH₂CH₂—NH—(CH₂)₉CH₃;    -   —CH₂CH₂CH₂—NH—(CH₂)₈CH₃;    -   —CH₂CH₂CH₂CH₂—NH—(CH₂)₇CH₃;    -   —CH₂CH₂—NHSO₂—(CH₂)₉CH₃;    -   —CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃;    -   —CH₂CH₂—S—(CH₂)₈CH₃;    -   —CH₂CH₂—S—(CH₂)₉CH₃;    -   —CH₂CH₂—S—(CH₂)₁₀CH₃;    -   —CH₂CH₂CH₂—S—(CH₂)₈CH₃;    -   —CH₂CH₂CH₂—S—(CH₂)₉CH₃;    -   —CH₂CH₂CH₂—S—(CH₂)₃—CH═CH—(CH₂)₄CH₃ (trans);    -   —CH₂CH₂CH₂CH₂—S—(CH₂)₇CH₃;    -   —CH₂CH₂—S(O)—(CH₂)₉CH₃;    -   —CH₂CH₂—S—(CH₂)₆Ph;    -   —CH₂CH₂—S—(CH₂)₈Ph;    -   —CH₂CH₂CH₂—S—(CH₂)₈Ph;    -   —CH₂CH₂—NH—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂—NH—CH₂-4-[4-CH₃)₂CHCH₂-]-Ph;    -   —CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)-Ph;    -   —CH₂CH₂—S—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂—S(O)—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂CH₂—S—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂CH₂—S(O)—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂CH₂—S—CH₂-4-[3,4-di-Cl-PhCH₂O—)-Ph;    -   —CH₂CH₂—NHSO₂—CH₂-4-[4-(4-Ph)-Ph]-Ph;    -   —CH₂CH₂CH₂—NHSO₂—CH₂-4-(4-Cl-Ph)-Ph;    -   —CH₂CH₂CH₂—NHSO₂—CH₂-4-(Ph-C≡C—)-Ph;    -   —CH₂CH₂CH₂—NHSO₂-4-(4-Cl-Ph)-Ph; and    -   —CH₂CH₂CH₂—NHSO₂-4-(naphth-2-yl)-Ph.

Other preferred —R^(a)—Y—R^(b)—(Z)_(x) groups are shown in Tables I-VIbelow.

In another of its composition aspects, this invention provides acompound of formula I:

wherein

R¹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, heterocyclic and —R^(a)—Y—R^(b)—(Z)_(x);or a saccharide group optionally substituted with—R^(a)—Y—R^(b)—(Z)_(x);

R² is hydrogen or a saccharide group optionally substituted with—R^(a)—Y—R^(b)—(Z)_(x);

R³ is —OR^(c), —NR^(c)R^(c), —O—R^(a)—Y—R^(b)—(Z)_(x), —NR^(c)R^(e), or—O—R^(e);

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,—R^(a)—Y—R^(b)—(Z)_(x), —C(O)R^(d) and a saccharide group optionallysubstituted with —R^(a)—Y—R^(b)—(Z)_(x);

R⁵ is selected from the group consisting of hydrogen, halo,—CH(R^(c))—NR^(c)R^(c), —CH(R^(c))—NR^(c)—R^(e) and—CH(R^(c))—NR^(c)—R^(a)—Y—R^(b)—(Z)_(x);

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,—R^(a)—Y—R^(b)—(Z)_(x), —C(O)R^(d) and a saccharide group optionallysubstituted with —NR^(c)—R^(a)—Y—R^(b)—(Z)_(x), or R⁵ and R⁶ can bejoined, together with the atoms to which they are attached, form aheterocyclic ring optionally substituted with—NR^(c)—R^(a)—Y—R^(b)—(Z)_(x);

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl,—R^(a)—Y—R^(b)—(Z)_(x), and —C(O)R^(d);

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; or R⁸ and R¹⁰ arejoined to form —Ar¹—O—Ar²—, where Ar¹ and Ar² are independently aryleneor heteroarylene;

R¹¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic, or R¹⁰ and R¹¹ arejoined, together with the carbon and nitrogen atoms to which they areattached, to form a heterocyclic ring;

R¹² is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, heterocyclic, —C(O)R^(d), —C(NH)R^(d),—C(O)NR^(c)R^(c), —C(O)OR^(d), —C(NH)NR^(c)R^(c) and—R^(a)—Y—R^(b)—(Z)_(x), or R¹¹ and R¹² are joined, together with thenitrogen atom to which they are attached, to form a heterocyclic ring;

R¹³ is selected from the group consisting of hydrogen or —OR¹⁴;

R¹⁴ is selected from hydrogen, —C(O)R^(d) and a saccharide group;

each R^(a) is independently selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,alkynylene and substituted alkynylene;

each R^(b) is independently selected from the group consisting of acovalent bond, alkylene, substituted alkylene, alkenylene, substitutedalkenylene, alkynylene and substituted alkynylene, provided R^(b) is nota covalent bond when Z is hydrogen;

each R^(c) is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclicand —C(O)R^(d);

each R^(d) is independently selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R^(e) is a saccharide group;

X¹, X² and X³ are independently selected from hydrogen or chloro;

each Y is independently selected from the group consisting of oxygen,sulfur, —S—S—, —NR^(c)—, —S(O)—, —SO₂—, —NR^(c)C(O)—, —OSO₂—, —OC(O)—,—NR^(c) SO₂—, —C(O)NR^(c)—, —C(O)O—, —SO₂NR^(c)—, —SO₂O—,—P(O)(OR^(c))O—, —P(O)(OR^(c))NR^(c)—,—OP(O)(OR^(c))O—,—OP(O)(OR^(c))NR^(c), —OC(O)O—, —NR^(c)C(O)O—,—NR^(c)C(O)NR^(c)—, —OC(O)NR^(c)— and —NR^(c)SO₂NR^(c)—;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

n is 0, 1 or 2;

x is 1 or 2;

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof;

provided that at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷ or R¹² has asubstitutent of the formula —R^(a)—Y—R^(b)—(Z)_(x);

and further provided that:

(i) when Y is —NR^(c)—, R^(c) is alkyl of 1 to 4 carbon atoms, Z ishydrogen and R^(b) is alkylene, then R^(b) contains at least 5 carbonatoms;

(ii) when Y is —C(O)NR^(c)—, Z is hydrogen and R^(b) is alkylene, thenR^(b) contains at least 5 carbon atoms;

(iii) when Y is sulfur, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 7 carbon atoms; and

(iv) when Y is oxygen, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 11 carbon atoms.

Preferably, R¹ is a saccharide group optionally substituted with—R^(a)—Y—R^(b)—(Z)_(x). More preferably, R¹ is a saccharide group of theformula:

wherein

R¹⁵ is —R^(a)—Y—R^(b)—(Z)_(x), where R^(a), R^(b), Y, Z and x are asdefined herein; and

R¹⁶ is hydrogen or methyl.

Preferably, R² is hydrogen.

R³ is preferably —OR^(c) or —NR^(c)R^(c); more preferably R³ is —OH.Particularly preferred R³ groups are those shown in Tables I-IV as R²².

Preferably, R⁴, R⁶ and R⁷ are each independently selected from hydrogenor —C(O)R^(d). More preferably, R⁴, R⁶ and R⁷ are each hydrogen.

R⁵ is preferably hydrogen, —CH₂—NHR^(c), —CH₂—NR^(c)R^(e) and—CH₂—NH—R^(a)—Y—R^(b)—(Z)_(x), where R^(a), R^(b), R^(c), R^(e), Y, Zand x are as defined herein. Particularly preferred R⁵ groups includehydrogen, —CH₂—N—(N—CH₃—D-glucamine); —CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—NH—(CH₂)₁₁CH₃; —CH₂—NH—(CH₂)₅—COOH; and—CH₂—N—(2-amino-2-deoxygluconic acid). Other preferred R⁵ groups arethose shown in Table III as R²³.

Preferably, R⁸ is —CH₂C(O)NH₂, —CH₂COOH, benzyl, 4-hydroxyphenyl or3-chloro-4-hydroxyphenyl. More preferably, R⁸ is —CH₂C(O)NH₂.

R⁹ is preferably hydrogen or alkyl. More preferably, R⁹ is hydrogen.

R¹⁰ is preferably alkyl or substituted alkyl. More preferably, R¹⁰ isthe side-chain of a naturally occurring amino acid. Still morepreferably, R¹⁰ is isobutyl.

R¹¹ is preferably hydrogen or alkyl. More preferably, R¹¹ is hydrogen ormethyl.

R¹² is preferably hydrogen, alkyl, substituted alkyl or —C(O)R^(d). Morepreferably, R¹² is hydrogen or —CH₂COOH. Other preferred R¹² groups arethose shown in Table II as R²⁷.

X¹ and X² are preferably chloro. X³ is preferably hydrogen.

Preferably, n is 0 or 1. More preferably, n is 1.

In still another of its composition aspects, this invention provides acompound of formula II:

wherein

R²¹is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, heterocyclic and —R^(a)—Y—R^(b)—(Z)_(x);or a saccharide group optionally substituted with—R^(a)—Y—R^(b)—(Z)_(x);

R²² is —OR^(c), —NR^(c)R^(c), —O—R^(a)—Y—R^(b)—(Z)_(x) or—NR^(c)—R^(a)—Y—R^(b)—(Z)_(x);

R²³ is selected from the group consisting of hydrogen, halo,—CH(R^(c))—NR^(c)R^(c), —CH(R^(c))—R^(e) and—CH(R^(c))—NR^(c)—R^(a)—Y—R^(b)—(Z)_(x);

R²⁴ is selected from the group consisting of hydrogen and lower alkyl;

R²⁵ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R²⁶ is selected from the group consisting of hydrogen and lower alkyl;or R²⁵ and R²⁶ are joined, together with the carbon and nitrogen atomsto which they are attached, to form a heterocyclic ring;

R²⁷ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, heterocyclic, —C(O)R^(d), —C(NH)R^(d),—C(O)NR^(c)R^(c), —C(O)OR^(d), —C(NH)NR^(c)R^(c) and—R^(a)—Y—R^(b)—(Z)_(x), or R²⁶ and R²⁷ are joined, together with thenitrogen atom to which they are attached, to form a heterocyclic ring;

each R^(a) is independently selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,alkynylene and substituted alkynylene;

each R^(b) is independently selected from the group consisting of acovalent bond, alkylene, substituted alkylene, alkenylene, substitutedalkenylene, alkynylene and substituted alkynylene, provided R^(b) is nota covalent bond when Z is hydrogen;

each R^(c) is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclicand —C(O)R^(d);

each R^(d) is independently selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R^(c) is an aminosaccharide group;

each Y is independently selected from the group consisting of oxygen,sulfur, —S—S—,—NR^(c)—, —S(O)—, —SO₂—, —NR^(c)C(O)—, —OSO₂—, —OC(O)—,—NR^(c)SO₂—, —C(O)NR^(c)—, —C(O)O—, —SO₂NR^(c)—, —SO₂O—,—P(O)(OR^(c))O—, —P(O)(OR^(c))NR^(c)—,—OP(O)(OR^(c))O—,—OP(O)(OR^(c))NR^(c)—, —OC(O)O—, —NR^(c)C(O)O—,—NR^(c)C(O)NR^(c)—, —OC(O)NR^(c)— and —NR^(c)SO₂NR^(c);

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

n is 0, 1 or 2;

x is 1 or 2;

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof;

provided that at least one of R²¹, R²², R²³ or R²⁷ has a substitutent ofthe formula —R^(a)—Y—R^(b)—(Z)_(x);

and further provided that:

(i) when Y is —NR^(c)—, R^(c) is alkyl of 1 to 4 carbon atoms, Z ishydrogen and R^(b) is alkylene, then R^(b) contains at least 5 carbonatoms;

(ii) when Y is —C(O)NR^(c)—, Z is hydrogen and R^(b) is alkylene, thenR^(b) contains at least 5 carbon atoms;

(iii) when Y is sulfur, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 7 carbon atoms; and

(iv) when Y is oxygen, Z is hydrogen and R^(b) is alkylene, then R^(b)contains at least 11 carbon atoms.

Preferably, R²¹ is a saccharide group of the formula:

wherein

R¹⁵ is —R^(a)—Y—R^(b)—(Z)_(x), where R^(a), R^(b), Y, Z and x are asdefined herein; and

R¹⁶ is hydrogen or methyl.

R²² is preferably —OR^(c) or —NR^(c)R^(c); more preferably R²² is —OH.Particularly preferred R²² groups are those shown in Tables I-IV.

R²³ is preferably hydrogen, —CH₂—R^(e), —CH₂—NHR^(c) and—CH₂—NH—R^(a)—Y—R^(b)—(Z)_(x), where R^(a), R^(b), R^(c), R^(e), Y, Zand x are as defined herein. Particularly preferred R²³ groups includehydrogen, CH₂N(N—CH₃—D-glucamine); —CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃;—CH₂—NH—CH₂CH₂—NH—(CH₂)₁₁CH₃; —CH₂—NH—(CH₂)₅—COOH; and—CH₂—N—(2-amino-2-deoxygluconic acid). Other preferred R²³ groups areshown in Table III.

R²⁴ is preferably hydrogen or alkyl. More preferably, R²⁴ is hydrogen.

R²⁵ is preferably alkyl or substituted alkyl. More preferably, R²⁵ isthe side-chain of a naturally occurring amino acid. Still morepreferably, R²⁵ is isobutyl.

R²⁶ is preferably hydrogen or alkyl. More preferably, R²⁶ is hydrogen ormethyl.

R²⁷ is preferably hydrogen, alkyl, substituted alkyl or —C(O)R^(d). Morepreferably, R²⁷ is hydrogen or —CH₂COOH. Other preferred R²⁷ groups arethose shown in Table II.

In yet another of its composition aspects, this invention provides apharmaceutical composition comprising a pharmaceutically-acceptablecarrier and a therapeutically effective amount of a glycopeptidecompound having at least one substituent of the formula:—R^(a)—Y—R^(b)—(Z)_(x)

wherein R^(a), R^(b), Y, Z and x are as defined herein.

Additionally, this invention provides a pharmaceutical compositioncomprising a pharmaceutically-acceptable carrier and a therapeuticallyeffective amount of a compound of formula I or II.

The compounds of this invention are highly effective antibacterialagents. Accordingly, in one of its method aspects, this inventionprovides a method of treating a mammal having a bacterial disease, themethod comprising administering to the mammal a therapeuticallyeffective amount of a glycopeptide compound having at least onesubstituent of the formula:

 —R^(a)—Y—R^(b)—(Z)_(x)

wherein R^(a), R^(b), Y, Z and x are as defined herein.

Additionally, this invention provides a method of treating a mammalhaving a bacterial disease, the method comprising administering to themammal a therapeutically effective amount of a compound of formula I orII.

This invention also provides processes for preparing glycopeptidederivatives, which processes are described further herein below.

In another of its aspects, this invention is directed to the use of aglycopeptide derivative of formula I or formula II in the manufacture ofa formulation or medicament for a medicinal treatment. Preferably, theformulation or medicament is used as an antibacterial agent.

Preferred compounds of this invention are those set forth in thefollowing tables as formulas III, IV, V, VI, VII and VIII, andpharmaceutically-acceptable salts thereof:

TABLE I III

R¹⁵ No. (R¹⁷ = H, unless otherwise indicated) R²² 1 —CH₂CH₂—NH—(CH₂)₉CH₃—OH 2 —CH₂CH₂—N[(CH₂)₉CH₃]₂ —OH 3 —CH₂CH₂—NH—(CH₂)₇CH₃ —OH 4—CH₂CH₂—NH—(CH₂)₅CH₃ —OH 5 —CH₂CH₂—NH—CH₂Ph —OH 6 —CH₂CH₂—NH—CH₂-4-Ph-Ph—OH 7 —CH₂CH₂—NH—CH₂-4-(4-Cl-Ph)-Ph —OH 8 —CH₂CH₂—NH—(CH₂)₈CH₃ —OH 9—CH₂CH₂—NH—CH₂-cyclohexyl —OH 10 —CH₂CH₂CH₂—NH—(CH₂)₈CH₃ —OH 11—CH₂CH₂CH₂CH₂—NH—(CH₂)₇CH₃ —OH 12 —CH₂CH₂CH₂CH₂CH₂—NH—(CH₂)₆CH₃ —OH 13—CH₂CH₂—N(CH₃)—(CH₂)₉CH₃ —OH 14 —CH₂CH₂—NH—(CH₂)₃CH═CH(CH₂)₄CH₃ (trans)—OH 15 —CH₂CH₂—NH—CH₂CH═C(CH₃)(CH₂)₂—CH═C(CH₃)₂ —OH (trans, trans) 16—CH₂CH₂—NH—(CH₂)₈CH(OH)CH₃ —OH 17 —CH₂CH₂—NH—(CH₂)₈CH═CH₂ —OH 18—CH₂CH₂—NH—CH₂-cyclopropyl —OH 19 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃N(CH₃)₂20 —CH₂CH₂—N[(CH₂)₉CH₃]₂ —NH(CH₂)₃N(CH₃)₂ 21 —CH₂CH₂—NH—(CH₂)₉CH₃—N-(D-glucosamine) 22 —CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂COOH 23—CH₂CH₂—NH—CH₂-4-(4-Cl-Ph)-Ph —N-(D-glucosamine) 24 —CH₂CH₂—NH—(CH₂)₈CH₃—N-(D-glucosamine) 25 —CH₂CH₂—NH—CH₂CH═C(CH₃)(CH₂)₂—CH═C(CH₃)₂—N-(D-glucosamine) (trans, trans) 26 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(CO₂CH₃)CH₂CO₂CH₃ 27 —CH₂CH₂—NH—(CH₂)₈CH(OH)CH₃ —NHCH(COOH)CH₂COOH28 —CH₂CH₂—NHC(O)—(CH₂)₆CH(CH₃)CH₃ —OH 29 —CH₂CH₂—NHC(O)—(CH₂)₈CH₃ —OH30 —CH₂CH₂—OC(O)—(CH₂)₈CH₃ —OH 31 —CH₂—C(O)O—(CH₂)₉CH₃ —OH 32—CH₂—C(O)NH—(CH₂)₉CH₃ —OH 33 —CH₂—C(O)O—(CH₂)₇CH₃ —OH 34—CH₂CH₂—NHSO₂—(CH₂)₇CH₃ —OH 35 —CH₂CH₂— OSO₂—(CH₂)₇CH₃ —OH 36—CH₂CH₂—S—(CH₂)₉CH₃ —OH 37 —CH₂CH₂—NHC(O)—(CH₂)₆CH₃ —OH 38—CH₂CH₂—NHC(O)—(CH₂)₇CH₃ —OH 39 —CH₂CH₂—NHC(O)—(CH₂)₉CH₃ —OH 40—CH₂—C(O)NH—(CH₂)₆CH₃ —OH 41 —CH₂—C(O)NH—(CH₂)₇CH₃ —OH 42—CH₂—C(O)NH—(CH₂)₈CH₃ —OH 43 —CH₂CH₂—NH—(CH₂)₉CH₃—NH(CH₂)₃-morpholin-4-yl 44 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃—NH—(CH₂)₂CH₃45 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₂-piperidin-1-yl 46 —CH₂CH₂—NH—(CH₂)₉CH₃—NH(CH₂)₄NHC(N)NH₂ 47 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₂—N⁺(CH₃)₃ 48—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)(CH₂)₃NHC(N)NH₂ 49 —CH₂CH₂—NH—(CH₂)₉CH₃—NH[(CH₂)₃NH—]₃H 50 —CH₂CH₂—NH—(CH₂)₉CH₃ —N[(CH₂)₃N(CH₃)₂]₂ 51—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃-imidiazol-1-yl 52 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH₂-4-pyridyl 53 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃CH₃ 54—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₂OH 55 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₅OH 56—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₂OCH₃ 57 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH₂-tetrahydrofuran-2-yl 58 —CH₂CH₂—NH—(CH₂)₉CH₃ —N[(CH₂)₂OH]₂ 59—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₂N[(CH₂)₂OH]₂ 60 —CH₂CH₂—NH—(CH₂)₉CH₃—N-(glucamine) 61 —CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH₂COOH 62—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂OH 63 —CH₂CH₂—NH—(CH₂)₉CH₃—NH(CH₂)₂COOH 64 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃SO₃H 65—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)(CH₂)₃COOH 66 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(COOH)(CH₂)₂NH₂ 67 —CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)(CH₂)₃NH₂ 68—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂CO₂(CH₂)₃—N⁺(CH₃)₃ 69—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂CO₂—(CH₂)₂C(O)N(CH₃)₂ 70—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂CO₂—(CH₂)₃-morpholin-4-yl 71—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂CO₂(CH₂)₂OC(O)C(CH₃)₃ 72—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(CH₂COOH)CO₂(CH₂)₃—N⁺(CH₃)₃ 73—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(CH₂COOH)CO₂(CH₂)₂C(O)N(CH₃)₂ 74—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(CH₂COOH)CO₂(CH₂)₃-morpholin-4-yl 75—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(CH₂COOH)CO₂(CH₂)₂OC(O)C(CH₃)₃ 76—CH₂CH₂—NH—(CH₂)₆Ph —OH 77 —CH₂CH₂—NH—(CH₂)₈Ph —OH 78 —CH₂CH₂—NH—CH₂Ph—OH 79 —CH₂CH₂—NH—CH₂-4-Cl-Ph —OH 80 —CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₂O—]Ph—OH 81 —CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₄O—]Ph —OH 82—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₆O—]Ph —OH 83 —CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₈O—]Ph—OH 84 —CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₂—]Ph —OH 85—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₃—]Ph —OH 86 —CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₄—]Ph—OH 87 —CH₂CH₂—NH—CH₂-4-(PhO—)Ph —OH 88 —CH₂CH₂—NH—CH₂-4-(PhS—)Ph —OH 89—CH₂CH₂—NH—CH₂-3-(PhO—)Ph —OH 90 —CH₂CH₂—NH—CH₂-4-(cyclohexyl-)Ph —OH 91—CH₂CH₂—NH—CH₂-4-{4-[CH₃(CH₂)₄O—]-Ph}-Ph —OH 92 —CH₂CH₂—NH—CH₂-4-CF₃-Ph—OH 93 —CH₂CH₂—NH—CH₂-4-(PhCH₂O—)Ph —OH 94—CH₂CH₂—NH—CH₂-4-(4-CH₃-PhCH₂O—)Ph —OH 95 —CH₂CH₂—NH—(CH₂)₇CH(CH₃)₂ —OH96 —(CH₂)₅—NH—(CH₂)₆CH₃ —OH 97 —(CH₂)₃—NH—(CH₂)₉CH₃ —OH 98—(CH₂)₄—NH—(CH₂)₉CH₃ —OH 99 —(CH₂)₅—NH—(CH₂)₉CH₃ —OH 100—CH₂CH₂—NH—(CH₂)₇CH₃ —OH 101 —CH₂CH₂—NH—CH₂-cyclohexyl —OH 102—CH₂CH₂—S—(CH₂)₇CH₃ —OH 103 —CH₂CH₂—OC(O)—(CH₂)₆CH₃ —OH 104—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —OH 105 —CH₂CH₂—OSO₂—(CH₂)₉CH₃ —OH 106—CH₂CH₂—NH—CH₂CH═CH—CH═CH(CH₂)₄CH₃ —OH (trans, trans) 107—CH₂CH₂—NH—CH₂CH═CH—CH═CH(CH₂)₃CH₃ —OH (trans, trans) 108—CH₂CH₂—NH—CH₂CH═CH—CH═CHCH₂CH₃ —OH (trans, trans) 109—CH₂CH₂—NH—CH₂CH═CH—CH₂CH₂CH═CHCH₂CH₃ —OH (trans, trans) 110—CH₂CH₂—NH—CH₂-4-Cl-Ph —OH 111 —CH₂CH₂—NH—CH₂-4-(PhCH₂O—)Ph —OH 112—CH₂CH₂—NH—CH₂-4-(4-CH₃-PhCH₂O—)Ph —OH 113—CH₂CH₂—NH—CH₂-4-(4-Cl-PhCH₂O—)Ph —OH 114—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₂O—]Ph —OH 115—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₄O—]Ph —OH 116—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₆O—]Ph —OH 117—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₈O—]Ph —OH 118—CH₂CH₂—NH—CH₂-4-[(CH₃)₂CHCH₂—]Ph —OH 119 —CH₂CH₂—NH—CH₂-4-(Ph-S—)Ph —OH120 —CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)-Ph —OH 121—CH₂CH₂—NH—CH₂-4-{4-[CH₃(CH₂)₄O—]-Ph}-Ph —OH 122 —CH₂CH₂—NH—(CH₂)₆Ph —OH123 —CH₂CH₂—NH—(CH₂)₈Ph —OH 124 —CH₂CH₂—NH—(CH₂)₉CH₃ R¹⁷ = —CH₂COOH —OH125 —CH₂CH₂—NH—(CH₂)₉CH₃ R¹⁷ = —CH₂[CH(OH)]₄COOH —OH 126—CH₂CH₂—NH—(CH₂)₉CH₃ R¹⁷ = —CH₂-(imidazol-4-yl) —OH 127—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃CH₃ 128 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(COOH)CH₂OH 129 —CH₂CH₂—NH—CH₂CH₂-(cyclopropyl) —OH 130—CH₂—C(O)O—(CH₂)₇CH₃ —OH 131 —CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂CO₂CH₃132 —CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(CH₂COOH)CO₂(CH₂)₂N(CH₃)₂ 133—CH₂CH₂—NH—CH₂CH═CH—CH═CHCH₃ (trans, trans) —OH 134 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(COOH)CH₂CO₂CH₂C(O)N(CH₃)₂ 135 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(CH₂COOH)CO₂CH₂C(O)N(CH₃)₂ 136 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH(CH₂COOH)CO₂CH₃ 137 —CH₂CH₂—NHC(O)—CH₂CH₂—C(O)NHCH₂CH₂NH₂—NHCH₂CH₂CH₂N(CH₃)₂ 138 —CH₂CH₂—NHSO₂-4-Ph-Ph —OH 139—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH₂CH₂CO₂CH₃ 140 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH[CH₂CO₂CH₂C(O)N(CH₃)₂]CO₂CH₂—C(O)— N(CH₃)₂ 141 —CH₂CH₂—NH—(CH₂)₉CH₃—NHCH₂CO₂CH₃ 142 —CH₂CH₂—NH—(CH₂)₉CH₃ —N-(methyl3-amino-3-deoxyamnnopyranoside) 143 —CH₂CH₂—NH—(CH₂)₉CH₃ —N-(methyl3-amino-2,3-6-trideoxyhexopyranoside) 144 —CH₂CH₂—NH—(CH₂)₉CH₃—N-[2-amino-2-deoxy-6-(dihydrogen phosphate)glucopyranose 145—CH₂CH₂—NH—(CH₂)₉CH₃ —N-(2-amino-2-deoxygluconic acid) 146—CH₂CH₂—N(C(O)CH₂NHCH₃)—(CH₂)₉CH₃ —OH 147 —CH₂CH₂—N(C(O)CH₃)—(CH₂)₉CH₃—OH 148 —CH₂CH₂—S(O)—(CH₂)₉CH₃ —OH 149 —CH₂CH₂—NH—(CD₂)₉CD₃ —OH 150—CH₂CH₂—N(CH₂COOH)—(CH₂)₉CH₃ —OH 151 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₄COOH152 —CH₂CH₂—NHSO₂-4-(4-Cl-Ph)-Ph —OH 153 —CH₂CH₂—N(CH₂CO₂CH₃)—(CH₂)₉CH₃—OH 154 —CH₂CH₂—NH—(CH₂)₉CH₃ —N—(N—CH₃-D-glucamine) 155—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₆COOH 156 —CH₂—C(O)O—CH₂CH₃ —OH 157—CH₂CH₂—S(O)—(CH₂)₇CH₃ —OH 158 —CH₂CH₂—NHSO₂-3-(4-Cl-Ph)-Ph —OH 159—CH₂CH₂—NHSO₂—(CH₂)₇CH₃ —OH 160 —CH₂CH₂CH₂—NHSO₂-4-(4-Cl-Ph)-Ph —OH 161—CH₂CH₂—NH—CH₂-4-(4-Cl-PhCH₂O—)-Ph —N-(D-glucosamine) 162—CH₂CH₂—NH—CH₂-4-(4-Cl-PhCH₂O—)-Ph —NHCH(COOH)CH₂COOH 163—CH₂CH₂—NHSO₂-4-(naphth-2-yl)-Ph —OH 164 —CH₂CH₂—NH—(CH₂)₁₁CH₃ —OH 165—CH₂CH₂—N[C(O)CH(NH₂)(CH₂)₄NH₂]—(CH₂)₉CH₃ —OH (R isomer) 166—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —O-(D-glucose) 167 —CH₂CH₂—NHSO₂—(CH₂)₉CH₃—N[(CH₂)₂OH]₂ 168 —CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)-Ph —O-(D-glucose) 169—CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)-Ph —N[(CH₂)₂OH]₂ 170—CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)-Ph —OH 171—CH₂CH₂CH₂—NH—CH₂-4-(4-CH₃O-Ph)-Ph —OH 172—CH₂CH₂—NH—CH₂-4-[(CH₃)₃CO]-Ph —OH 173—CH₂CH₂—NH—CH₂-3,4-di-(CH₃CH₂O)-Ph —OH 174—CH₂CH₂—NH—CH₂-4-[(CH₃)₂CH]-Ph —OH 175—CH₂CH₂—NH—CH₂-4-[CH₃(CH₂)₃C≡C]-Ph —OH 176—CH₂CH₂—NH—CH₂-4-[(CH₃)₂CHO]-Ph —OH 177 —CH₂CH₂—NH—CH₂-4-(PhC≡C)-Ph —OH178 —CH₂CH₂—NH—CH₂-4-[(CH₃)₃C]-Ph —OH 179—CH₂CH₂—NH—CH₂-5-(PhC≡C)-thiophen-2-yl —OH 180—CH₂CH₂—NH—CH₂-4-(PhCH═CH—)Ph (trans) —OH 181—CH₂CH₂—NH—CH₂—(CH═CH)₄—CH₃ —OH (trans, trans, trans, trans) 182—CH₂CH₂—N(C(O)Ph)-(CH₂)₉CH₃ —OH 183—CH₂CH₂—NH—CH₂-4-[4-(CH₃)₃C-thiazol-2-yl]-Ph —OH 184—CH₂CH₂—N[(CH₂)₉CH₃]—C(O)CH₂-S-4-pyridyl —OH 185—CH₂CH₂—N[(CH₂)₉CH₃]-C(O)-2-[PhCH(CH₃)NHC(O)—]Ph —OH (R isomer) 186—CH₂CH₂—N[(CH₂)₉CH₃]—C(O)-(1-PhCH₂OC(O)-2- —OH oxoimidazolidin-5-yl) (Sisomer) 187 —CH₂CH₂—N[(CH₂)₉CH₃]—C(O)-1-HO-cyclopropyl —OH 188—CH₂CH₂—N(C(O)CH₂-naphth-2-yl)-(CH₂)₉CH₃ —OH 189—CH₂CH₂—N[C(O)(CH₂)₉CH₂OH]—(CH₂)₉CH₃ —OH 190—CH₂CH₂—N[C(O)CH₂(OCH₂CH₂)₂OCH₃]—(CH₂)₉CH₃ —OH 191—CH₂CH₂—N[C(O)CH₂CH(Ph)₂]—(CH₂)₉CH₃ —OH 192—CH₂CH₂—N(C(O)CH₂-3-HO-Ph)-(CH₂)₉CH₃ —OH 193—CH₂CH₂—N(C(O)CH₂—NHC(O)-3-CH₃-Ph)-(CH₂)₉CH₃ —OH 194—CH₂CH₂—N(C(O)CH₂CH₂—O-Ph)-(CH₂)₉CH₃ —OH 195—CH₂CH₂—N(C(O)CH₂CH₂-3-pyridyl)-(CH₂)₉CH₃ —OH 196—CH₂CH₂—N(C(O)(CH₂)₃-4-CH₃O-Ph)-(CH₂)₉CH₃ —OH 197—CH₂CH₂—N(C(O)-indol-2-yl)-(CH₂)₉CH₃ —OH 198—CH₂CH₂—N{C(O)-1-[CH₃COC(O)—]-pyrrolidin-2-yl}- —OH (CH₂)₉CH₃ 199—CH₂CH₂—N(C(O)CH₂-NHC(O)-CH═CH-furan-2-yl)- —OH (CH₂)₉CH₃ (trans) 200—CH₂CH₂—N[C(O)-1-CH₃CH₂-7-CH₃-4-oxo-1,4- —OHdihydro[1,8]naphthyridin-3-yl]-(CH₂)₉CH₃ 201—CH₂CH₂—N(C(O)-1,3-benzodioxol-5-yl)-(CH₂)₉CH₃ —OH 202—CH₂CH₂—N(C(O)CH₂-4-oxo-2-thiooxothiazolidin-3-yl)- —OH (CH₂)₉CH₃ 203—CH₂CH₂—N(C(O)-3,4,5-tri-HO-cyclohex-1-en-1-yl)- —OH (CH₂)₉CH₃ (R,S,Risomer) 204 —CH₂CH₂—N(C(O)CH₂CH₂C(O)NH₂)—(CH₂)₉CH₃ —OH 205—CH₂CH₂—N(C(O)CH₂-5-CH₃-2,4-dioxo-3,4- —OHdihydropyrimidin-1-yl)-(CH₂)₉CH₃ 206—CH₂CH₂—N(C(O)CH═CH-imidazol-4-yl)-(CH₂)₉CH₃ —OH (trans) 207—CH₂CH₂—N[C(O)CH(CH₂CH₂C(O)NH₂)—NHC(O)O—CH₂Ph]- —OH (CH₂)₉CH₃ (S isomer)208 —CH₂CH₂—N[C(O)CH(CH₂OH)NHC(O)O—CH₂Ph]-(CH₂)₉CH₃ —OH (S isomer) 209—CH₂CH₂—N[C(O)CH[CH(OH)CH₃]NH—C(O)O—CH₂Ph]- —OH (CH₂)₉CH₃ (S isomer) 200—CH₂CH₂—N(C(O)CH₂NHSO₂-4-CH₃-Ph)-(CH₂)₉CH₃ —OH 211—CH₂CH₂—N(C(O)(CH₂)₃—NH₂)—(CH₂)₉CH₃ —OH 212—CH₂CH₂—N(C(O)-pyrrolidin-2-yl)-(CH₂)₉CH₃ —OH (R isomer) 213—CH₂CH₂—N(C(O)-pyrrolidin-2-yl)-(CH₂)₉CH₃ —OH (S isomer) 214—CH₂CH₂—N(C(O)CH(NH₂)(CH₂)₄—NH₂)-(CH₂)₉CH₃ —OH (S isomer) 215—CH₂CH₂—N(C(O)CH(NH₂)CH₂-3-HO-Ph)-(CH₂)₉CH₃ —OH 216—CH₂CH₂—N(C(O)CH(NH₂)CH₃)—(CH₂)₉CH₃ —OH (R isomer) 217—CH₂CH₂—N[C(O)CH(CH₂OH)NHC(O)—CH₃]—(CH₂)₉CH₃ —OH (S isomer) 218—CH₂CH₂—N[C(O)CH(NHC(O)CH₃)—(CH₂)₃—NHC(NH)NH₂]— —OH (CH₂)₉CH₃ (S isomer)219 —CH₂CH₂—N(C(O)CH₂NHC(O)CH₃)—(CH₂)₉CH₃ —OH 220—CH₂CH₂—N(C(O)CH(CH₃)OC(O)CH—(NH₂)CH₃)—(CH₂)₉CH₃ —OH (R,R isomer) 221—CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₃OC(O)CH(NH₂)CH₃ 222—CH₂CH₂—N(C(O)-5-oxopyrrolidin-2-yl)-(CH₂)₉CH₃ —OH (R isomer) 223—CH₂CH₂—NHC(O)—CH₂CH(CH₂CH₂Ph)-{3-[4-(9H-fluroen-9- —OHylCH₂OC(O)NH(CH₂)₄—]-1,4-dioxohexahydro-1,2-α-pyrazin-2- yl} (S,S,Sisomer) 224 —CH₂CH₂—NH—(CH₂)₉CH₃ —NH(CH₂)₄CH(C(O)-2-HOOC-pyrrolidin-1-yl)NHCH(COOH)—CH₂CH₂Ph (S,S isomer) 225 —CH₂CH₂—NHSO₂-4-(2-Cl-Ph)-Ph —OH226 —CH₂CH₂—NHSO₂-4-[4-(CH₃)₃C-Ph]-Ph —OH 227—CH₂CH₂—NHSO₂-4-[4-(Ph)-Ph-]Ph —OH 228 —CH₂CH₂—NH-4-(4-CF₃-Ph)-Ph —OH229 —CH₂CH₂—S—(CH₂)₈Ph —OH 230 —CH₂CH₂—S—(CH₂)₃CH═CH(CH₂)₄CH₃ —OH(trans) 231 —CH₂CH₂—S—CH₂CH₂(CF₂)₅CF₃ —OH 232—CH₂CH₂—S—CH₂-4-[(CH₃)₂CHCH₂—]Ph —OH 233 —CH₂CH₂—S—(CH₂)₁₁CH₃ —OH 234—CH₂CH₂—S—(CH₂)₈CH₃ —OH 235 —CH₂CH₂—S—CH₂-3,4-di-(PhCH₂O—)Ph —OH 236—CH₂CH₂CH₂—S—(CH₂)₈Ph —OH 237 —CH₂CH₂CH₂—S—(CH₂)₈CH₃ —OH 238—CH₂CH₂CH₂—S—(CH₂)₉CH₃ —OH 239 —CH₂CH₂CH₂—S—(CH₂)₆Ph —OH 240—CH₂CH₂CH₂CH₂—S—(CH₂)₇CH₃ —OH 241 —CH₂CH₂—S—(CH₂)₆Ph —OH 242—CH₂CH₂—S—(CH₂)₁₀Ph —OH 243 —CH₂CH₂CH₂—S—CH₂-4-[(CH₃)₂CHCH₂—]Ph —OH 244—CH₂CH₂—S—(CH₂)₃CH═CH(CH₂)₄CH₃ —OH (trans) 245—CH₂CH₂—S—CH₂-4-[3,4-di-Cl-PhCH₂O—]Ph —OH 246—CH₂CH₂CH₂—S—CH₂-4-[3,4-di-Cl-PhCH₂O—]Ph —OH 247—CH₂CH₂—SO-4-(4-Cl-Ph)-Ph —OH 248 —CH₂CH₂CH₂—SO-4-(4-Cl-Ph)-Ph —OH 249—CH₂CH₂—S—(CH₂)₁₀CH₃ —OH 250 —CH₂CH₂CH₂—S—(CH₂)₁₀CH₃ —OH 251—CH₂CH₂CH₂—S—CH₂-4-[CH₃(CH₂)₄O—]Ph —OH 252—CH₂CH₂CH₂—S—CH₂CH═CH—CH═CH(CH₂)₄CH₃ —OH (trans, trans) 253—CH₂CH₂—S—CH₂-4-[4-Cl-PhCH₂O—]Ph —OH 254—CH₂CH₂CH₂—S—CH₂-4-[4-Cl-PhCH₂O—]Ph —OH 255 —CH₂CH₂—NH—(CH₂)₉CH₃tetrazol-5-yl 256 —CH₂CH₂—S—(CH₂)₉CH₃ —N-(D-glucosamine) 257—CH₂CH₂CH₂—S—CH₂-4-(4-CF₃-Ph-)Ph —OH 258 —CH₂CH₂—S—(CH₂)₉CH₃tetrazol-5-yl 259 —CH₂CH₂CH₂—S—CH₂-4-(4-F-PhSO₂NH—)Ph —OH 260—CH₂CH₂CH₂—S—(CH₂)₈CH₃ —OH 261 —CH₂CH₂CH₂—S(O)—(CH₂)₆Ph —OH 262—CH₂CH₂—S(O)—(CH₂)₈Ph —OH 263 —CH₂CH₂—S—(CH₂)₃-4-Cl-Ph —OH 264—CH₂CH₂—S—(CH₂)₆-4-Cl-Ph —OH 265 —CH₂CH₂—SO₂—(CH₂)₉CH₃ —OH 421 —H—NH—CH₂CH₂—NH—(CH₂)₉CH₃ Ph = phenyl

TABLE II IV

R¹⁵ No. (R¹⁷ = H, unless otherwise indicated) R²² R²⁷ 266—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—[CH(OH)]₅CH₂OH 267 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —CH₂CH(OH)CH₂OH 268 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂CH₂NH₂ 269—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂C(O)OCH₂CH₃ 270 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—CH₂COOH 271 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂COOH R¹⁷ = —CH₂COOH 272—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂-2-pyridyl 273 —CH₂CH₂—NH—(CH₂)₈CH₃ —OH—CH₂[CH(OH)]₄COOH 274 —H —NHCH₂C(O)CH₂C(O)N(CH₃)₂ —H 275—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂-3-HOOC-Ph 276 —CH₂CH₂—N(C(O)CH(NH₂)— —OH—C(O)CH(NH₂)(CH₂)₄NH₂ (CH₂)₄NH₂)—(CH₂)₉CH₃ (R isomer) (R isomer) 277—CH₂CH₂—NH—(CH₂)₁₁CH₃ —OH —CH₂COOH 278 —CH₂CH₂—N(C(O)Ph)-(CH₂)₉CH₃ —OH—C(O)Ph 279 —CH₂CH₂—N(C(O)CH₂NHC(O)CH₃)— —OH —C(O)CH₂NHC(O)CH₃ (CH₂)₉CH₃280 —CH₂CH₂—S—(CH₂)₃CH═CH(CH₂)₄CH₃ —OH —CH₂CH₂—S—(CH₂)₃CH═CH(CH₂)₄CH₃(trans) (trans) 281 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₃ Ph = phenyl

TABLE III V

No. R¹⁵ R²² R²³ 282 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine)283 —CH₂CH₂—NH—CH₂-4-(4-Cl-Ph)Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 284—CH₂CH₂—NH—(CH₂)₈CH(OH)CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 285—CH₂CH₂—NH—(CH₂)₉CH₃ —N-(-D-glucosamine) —CH₂—N—(N—CH₃-D-glucamine) 286—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 287 —H —OH—CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃ 288 —CH₂CH₂—NH—CH₂-4-(4-Cl-Ph)Ph —OH—CH₂—N—(N—CH₃-D-glucamine) 289 —H —NH—(CH₂)₃—N(CH₃)₂—CH₂—NH—CH₂CH₂—NHC(O)—(CH₂)₃COOH 290 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—CH₂—NH—(CH₂)₉CH₃ 291 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—CH₂CH₂—COOH 292—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₅—COOH 293 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —CH₂-(morpholin-4-yl) 294 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—CH₂—NH—CH₂CH₂—O—CH₂CH₂OH 295 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—CH₂—NH—CH₂CH(OH)CH₂OH 296 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N[CH₂CH₂OH]₂297 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₃—N(CH₃)₂ 298—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N[(CH₂)₃—N(CH₃)₂]₂ 299—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₃-(imidazol-1-yl) 300—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₃-(morpholin-4-yl) 301—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₄—NHC(NH)NH₂ 302—CH₂CH₂—NHSO₂—(CH₂)₇CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 303—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 304—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂COOH —CH₂—N—(N—CH₃-D-glucamine) 305—CH₂CH₂—NH—(CH₂)₇CH(OH)CH₂CH₃ —OH -3,5-di-HO-4-[-CH₂—N—(N—CH₃-D-glucamine)]Ph 306 —CH₂CH₂—NH—(CH₂)₁₀OH —OH —CH₂—N—(N—CH₃-D-glucamine)307 —CH₂CH₂—NHSO₂-4-Ph-Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 308—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 309—CH₂CH₂—NH—(CH₂)₇CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 310—CH₂CH₂—NH—(CD₂)₉CD₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 311—CH₂CH₂—S—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 312—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—N-(2-amino-2-deoxygluconic acid) 313 —H—OH —CH₂—NH—CH₂CH₂—NH—(CH₂)₇CH₃ 314 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—CH₂—NHCH(COOH)CH₂COOH 315 —H —OH —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₇CH₃ 316 —H—OH —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ 317 —H —OH—CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃ 318 —H —OH —CH₂—NH—CH₂CH₂—NH—(CH₂)₇CH₃319 —CH₂CH₂—SO—(CH₂)₉CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 320—CH₂CH₂—NHSO₂—CH₂-4-(4-Cl-Ph)Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 321—CH₂CH₂—NH—CH₂CH═CH— —OH —CH₂—N—(N—CH₃-D-glucamine) CH═CH(CH₂)₄CH₃(trans, trans) 322 —CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —OH —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH323 —CH₂CH₂CH₂—NHSO₂—CH₂-4-(4-Cl-Ph)Ph —OH —CH₂—N—(N—CH₃-D-glucamine)324 —CH₂CH₂—NH—CH₂-4-[(CH₃)₂CHCH₂-]Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 325—CH₂CH₂—NH—CH₂-4-[(CH₃)₂CHCH₂-]Ph —OH —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH 326—CH₂CH₂—NH—CH₂-4-[4-Cl—PhCH₂O-]Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 327—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NHCH₂CH₂C(O)—N-(D-glucosamine) 328—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH 329—CH₂CH₂—NH—(CH₂)₉CH₃ —NHCH(COOH)CH₂COOH —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH 330—CH₂CH₂—NH—(CH₂)₁₁CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 331—CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)Ph —OH —CH₂—NH—CH₂CH₂—O—CH₂CH₂OH 332—CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 333—CH₂CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)Ph —OH —CH₂—NH—(CH₂)₃-(imidazol-1-yl) 334—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —OH —CH₂—NH—(6-oxo-[1,3]oxazinan-3-yl) 335—CH₂CH₂—NH—(CH₂)₈CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) 336—CH₂CH₂—NHSO₂—(CH₂)₉CH₃ —OH —CH₂—NH—(CH₂)₃-(imidazol-1-yl) 337 —H—N-(D-glucosamine) —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃ 338 —H —OH—CH₂—NH—CH₂CH₂—S—(CH₂)₇CH₃ 339 —H —OH —CH₂—NH—CH₂CH₂—S—(CH₂)₈CH₃ 340 —H—OH —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₈CH₃ 341 —H —OH —CH₂—NH—CH₂CH₂—S—(CH₂)₉CH₃342 —H —OH —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₇CH₃ 343—CH₂CH₂—NH—CH₂-4-(4-CF₃-Ph)Ph —OH —CH₂—N—(N—CH₃-D-glucamine) 344 —H —OH—CH₂—NH—CH₂CH₂—S—(CH₂)₁₁CH₃ 345 —H —OH —CH₂—NH—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃346 —H —OH —CH₂—NH—CH₂CH₂—S—(CH₂)₆Ph 347 —H —OH—CH₂—NH—CH₂CH₂—S—(CH₂)₈Ph 348 —H —OH —CH₂—NH—CH₂CH₂—S—(CH₂)₁₀Ph 349 —H—OH —CH₂—NH—CH₂CH₂—S—CH₂-4-(4-CF₃-Ph)Ph 350 —CH₂CH₂—S—(CH₂)₈Ph —OH—CH₂—N—(N—CH₃-D-glucamine) 351 —H —OH —CH₂—NH—CH₂CH₂—SO₂—(CH₂)₁₁CH₃ 352—CH₂CH₂—S—(CH₂)₈CH₃ —OH —CH₂—N—(N—CH₃-D-glucamine) Ph = phenyl

TABLE IV VI

R¹⁵ No. (R²³ = H, unless otherwise indicated) R²² R²⁷ 353—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —H 354 —H —OH —CH₂CH₂—NH—(CH₂)₉CH₃ 355—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —CH₂CH₂—NH—(CH₂)₉CH₃ 356 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —H R23 = —CH₂—N—(N—CH₃-D-glucamine) 357 —CH₂CH₂—NH—(CH₂)₉CH₃—N-(D-glucosamine) —H 358 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —(CH₂)₃CH(CH₃)₂ 359—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂CH₂CH(CH₃)₂ 360 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —C(O)CH(NH₂)(CH₂)₄NH₂ (R isomer) 361 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH(NH₂)(CH₂)₄NH₂ (S isomer) 362 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH(NH₂)(CH₂)₂COOH (R isomer) 363 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(NH)NH₂364 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂-(imidazol-4-yl) (R isomer)365 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂—COOH (R isomer) 366—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH(CH₃)CH₂CH₃ (S isomer) 367—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)NHCH₂CH(CH₃)₂ 368 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(NH)CH₂CH(CH₃)₂ 369 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂-Ph (Risomer) 370 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂NHCH₃ 371—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂-3-HO-Ph 372—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂-3-HO-Ph 373—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-2-[PhCH(CH₃)NHC(O)-]Ph (R isomer) 374—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-[1-PhC(O)-2-oxoimidazolidin-5-yl] (Sisomer) 375 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂-(1-HO-cycloprop-1-yl) 376—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂-(naphth-2-yl) 377 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —C(O)(CH₂)₉—OH 378 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-2,4-di-HO-Ph 379—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-2,6-di-HO-3-pyridyl 380—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂—O—CH₂CH₂—O—CH₂CH₂OCH₃ 381—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂CH(Ph)₂ 382 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH₂-3-HO-Ph 383 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂—NHC(O)-3-CH₃-Ph384 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂CH₂—O-Ph 385 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —C(O)CH₂CH₂-3-pyridyl 386 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH₂CH₂CH₂-4-CH₃O-Ph 387 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)-(3H-benzotriazol-5-yl) 388 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)-[1-(CH₃)₃COC(O)-pyrrolidin-2-yl) (S isomer) 389—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂CH₂CH₂-cyclohexyl 390—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-(1H-indol-2-yl) 391 —CH₂CH₂—NH—(CH₂)₉CH₃—OH —C(O)CH₂NHC(O)-furan-2-yl 392 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH(NHC(O)CH₃)CH₂-4-HO-Ph (S isomer) 393 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH₂NHC(O)CH═CH-furan-2-yl (trans) 394 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)-(1-CH₃CH₂-7-CH₃-4-oxo-1,4- dihydro[1,8]naphthyridin-3-yl) 395—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-2,3,4,5,6-penta-F-Ph 396—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-(1,3-benzodioxol-5-yl) 397—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂-(4-oxo-2-thiooxothiazolidin-3-yl) 398—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)-(3,4,5-tri-HO-cyclohex-1-enyl) 399—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂CH₂C(O)NH₂ 400 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH₂-(5-CH₃-2,4-dioxo-3,4-dihydropyrimidin-1-yl) 401—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH(CH₃)₂ (R isomer) 402—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH(NH₂)CH₂C(O)-(2-H₂N-Ph) 403—CH₂CH₂—NH—(CH₂)₉CH₃ —OH —C(O)CH₂—NH₂ 404 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH(NHCH₃)CH₂CH(CH₃)₂ (S isomer) 405 —CH₂CH₂—NH—(CH₂)₉CH₃ —OH—C(O)CH(NH₂)CH₂CH(CH₃)₂ (S isomer) Ph = phenyl

TABLE V VIIa

and/or VIIb

No. R¹⁸ 406 —CH₂CH₂—NHSO₂—(CH₂)₇CH₃ 407 —CH₂CH₂—NHSO₂—(CH₂)₉CH₃ 408—CH₂CH₂—NHSO₂—(CH₂)₁₁CH₃ 409 —CH₂CH₂—S—(CH₂)₇CH₃CH₂ 410—CH₂CH₂—S—(CH₂)₈CH₃ 411 —CH₂CH₂CH₂—NHSO₂—(CH₂)₉CH₃ 412—CH₂CH₂—S—(CH₂)₉CH₃ 413 —CH₂CH₂CH₂—NHSO₂—(CH₂)₇CH₃ 414—CH₂CH₂—S—(CH₂)₁₁CH₃ 415 —CH₂CH₂—S—(CH₂)₆Ph 416 —CH₂CH₂—S—(CH₂)₈Ph 417—CH₂CH₂—S—(CH₂)₁₀Ph 418 —CH₂CH₂—S—CH₂-4-(CF₃-Ph)-Ph Ph = phenyl

TABLE VI VIII

No. R¹⁹ 419 —CH₂CH₂CH₂—NH—(CH₂)₇CH₃ 420 —CH₂C(O)OC(CH₃)₃ 422—CH₂CH₂—NH—(CH₂)₉CH₃

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel derivatives of glycopeptide antibioticsand to pharmaceutical compositions and methods employing suchglycopeptide derivatives. When describing the compounds, compositionsand methods of this invention, the following terms have the followingmeanings, unless otherwise indicated.

Definitions

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 40 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to an alkyl group as defined above,having from 1 to 8 substituents, preferably 1 to 5 substitutents, andmore preferably 1 to 3 substituents, selected from the group consistingof alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 40 carbonatoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms.This term is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

The term “substituted alkylene” refers to an alkylene group, as definedabove, having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkylene groupsinclude those where 2 substituents on the alkylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkylene group. Preferably such fused groups contain from 1 to 3fused ring structures. Additionally, the term substituted alkyleneincludes alkylene groups in which from 1 to 5 of the alkylene carbonatoms are replaced with oxygen, sulfur or —NR— where R is hydrogen oralkyl. Examples of substituted alkylenes are chloromethylene (—CH(Cl)—),aminoethylene (—CH(NH₂)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—) and the like.

The term “alkaryl” refers to the groups -alkylene-aryl and -substitutedalkylene-aryl where alkylene, substituted alkylene and aryl are definedherein. Such alkaryl groups are exemplified by benzyl, phenethyl and thelike.

The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way ofexample, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy(—CH₂—O—C(CH₃)₃) and the like.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, byway of example, methylenethiomethoxy (—CH₂SCH₃), ethylenethiomethoxy(—CH₂CH₂SCH₃), n-propylene-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylene-t-thiobutoxy (—CH₂SC(CH₃)₃) and the like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH₂CH—CH— and—C(CH₃)═CH—) and the like.

The term “substituted alkenylene” refers to an alkenylene group asdefined above having from 1 to 5 substituents, and preferably from 1 to3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkenylene groupsinclude those where 2 substituents on the alkenylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkenylene group.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbonpreferably having from 2 to 40 carbon atoms, more preferably 2 to 20carbon atoms and even more preferably 2 to 6 carbon atoms and having atleast 1 and preferably from 1-6 sites of acetylene (triple bond)unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH) and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon preferably having from 2 to 40 carbon atoms, more preferably2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynylene groups include ethynylene(—C≡C—), propargylene (—CH₂C≡C—) and the like.

The term “substituted alkynylene” refers to an alkynylene group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —O-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl

The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “acylamino” or “aminocarbonyl” refers to the group —C(O)NRRwhere each R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic or where both R groups are joined to form aheterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl,aryl, heteroaryl and heterocyclic are as defined herein.

The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

The term “aminoacyloxy” or “alkoxycarbonylamino” refers to the group—NRC(O)OR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferredaryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with from 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, sulfonamide,thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

The term “arylene” refers to the diradical derived from aryl (includingsubstituted aryl) as defined above and is exemplified by 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic provided thatboth R's are not hydrogen.

“Amino acid” refers to any of the naturally occurring amino acids, aswell as synthetic analogs and derivatives thereof. α-Amino acidscomprise a carbon atom to which is bonded an amino group, a carboxygroup, a hydrogen atom, and a distinctive group referred to as a “sidechain”. The side chains of naturally occurring amino acids are wellknown in the art and include, for example, hydrogen (e.g., as inglycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine,proline), substituted alkyl (e.g., as in threonine, serine, methionine,cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine,and lysine), alkaryl (e.g., as in phenylalanine and tryptophan),substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g.,as in histidine).

The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”,“—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substitutedalkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl alkynyl are asdefined herein.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 20carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and thelike.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to alkyl as defined herein substituted by 1-4 halogroups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfurwithin at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl,pyrrolyl and furyl.

“Heteroarylalkyl” refers to (heteroaryl)alkyl—where heteroaryl and alkylare as defined herein. Representative examples include 2-pyridylmethyland the like.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heteroarylene” refers to the diradical group derived fromheteroaryl (including substituted heteroaryl), as defined above, and isexemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl and the like.

The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated unsaturated group having a single ring or multiple condensedrings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1 to 3 substituents, selected from the groupconsisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Suchheterocyclic groups can have a single ring or multiple condensed rings.Preferred heterocyclics include morpholino, piperidinyl, and the like.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

Another class of heterocyclics is known as “crown compounds” whichrefers to a specific class of heterocyclic compounds having one or morerepeating units of the formula [—(CH₂—)_(a)A—] where a is equal to orgreater than 2, and A at each separate occurrence can be O, N, S or P.Examples of crown compounds include, by way of example only,[—(CH₂)₃—NH—]₃, [—((CH₂)₂—O)₄—((CH₂)₂NH)₂] and the like. Typically suchcrown compounds can have from 4 to 10 heteroatoms and 8 to 40 carbonatoms.

The term “heterocyclooxy” refers to the group heterocyclic-O—.

The term “thioheterocyclooxy” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein, and is exemplified by the groups2,6-morpholino, 2,5-morpholino and the like.

The term “oxyacylamino” or “aminocarbonyloxy” refers to the group—OC(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “saccharide group” refers to an oxidized, reduced orsubstituted saccharide monoradical covalently attached to theglycopeptide or other compound via any atom of the saccharide moiety,preferably via the aglycone carbon atom. Respresentative saccharidesinclude, by way of illustration, hexoses such as D-glucose, D-mannose,D-xylose, D-galactose, vancosamine, 3-desmethyl-vancosamine,3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine,daunosamine, 3-epi-daunosamine, ristosamine, N-methyl-D-glucamine,D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine,sialyic acid, iduronic acid, L-fucose, and the like; pentoses such asD-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose;disaccharides such as 2-O-(α-L-vancosaminyl)-β-D-glucopyranose,2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose,or maltose; derivatives such as acetals, amines, acylated, sulfated andphosphorylated sugars; oligosaccharides having from 2 to 10 saccharideunits. For the purposes of this definition, these saccharides arereferenced using conventional three letter nomenclature and thesaccharides can be either in their open or preferably in their pyranoseform.

The term “amino-containing saccharide group” refers to a saccharidegroup having an amino substituent. Representative amino-containingsaccharides include L-vancosamine, 3-desmethyl-vancosamine,3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine,daunosamine, 3-epi-daunosamine, ristosamine, N-methyl-D-glucamine andthe like.

The term “spiro-attached cycloalkyl group” refers to a cycloalkyl groupattached to another ring via one carbon atom common to both rings.

The term “sulfonamide” refers to a group of the formula —SO₂NRR, whereeach R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic are as defined herein.

The term “thiol” refers to the group —SH.

The term “thioalkoxy” refers to the group —S-alkyl.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined above including optionally substituted aryl groupsalso defined above.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined above including optionallysubstituted aryl groups as also defined above.

As to any of the above groups which contain one or more substituents, itis understood, of course, that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisinvention include all stereochemical isomers arising from thesubstitution of these compounds.

“Glycopeptide” refers to heptapeptide antibiotics, characterized by amulti-ring peptide core optionally substituted with saccharide groups,such as vancomycin. Examples of glycopeptides included in thisdefinition may be found in “Glycopeptides Classification, Occurrence,and Discovery”, by Raymond C. Rao and Louise W. Crandall, (“Drugs andthe Pharmaceutical Sciences”Volume 63, edited by Ramakrishnan Nagarajan,published by Marcal Dekker, Inc.), which is hereby incorporated byreference in its entirety. Representative glycopeptides include thoseidentified as A477, A35512, A40926, A41030, A42867, A47934, A80407,A82846, A83850 ,A84575, AB-65, Actaplanin, Actinoidin, Ardacin,Avoparcin, Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin,Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin, Helvecardin,Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761,MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653,Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin,UK-68597, UK-69542, UK-72051, Vancomycin, and the like. The term“glycopeptide” as used herein is also intended to include the generalclass of peptides disclosed above on which the sugar moiety is absent,i.e. the aglycone series of glycopeptides. For example, removal of thedisaccharide moiety appended to the phenol on vancomycin by mildhydrolysis gives vancomycin aglycone. Also within the scope of theinvention are glycopeptides that have been further appended withadditional saccharide residues, especially aminoglycosides, in a mannersimilar to vancosamine.

“Vancomycin” refers to a glycopeptide antibiotic having the formula:

When describing vancomycin derivatives, the term “N^(van)—” indicatesthat a substituent is covalently attached to the amino group of thevacosamine moiety of vacomycin. Similarly, the term “N^(leu)—” indicatesthat a substituent is covalently attached to the amino group of theleucine moiety of vancomycin.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted” means that a groupmay or may not be substituted with the described substitutent.

“Transglycosylase enzyme substrate” as used herein denotes the moleculartarget of the transglycosylase enzyme. The substrate binds to the enzymeand eventually results in synthesis of the bacterial cell wall. Theaction of this enzyme is inhibited by a ligand domain that binds to theenzyme substrate. A ligand such as vancomycin binds to this substrateand in effect “sequesters” the substrate to prevent its recognition bythe enzyme and subsequent use in the construction of the bacterial cellwall.

“Potency” as used herein refers to the minimum concentration at which acompound or ligand is able to achieve a desirable biological ortherapeutic effect. The potency of a compound or ligand is typicallyproportional to its affinity for its binding site. In some cases, thepotency may be non-linearly correlated with its affinity

As used herein, the terms “inert organic solvent” or “inert solvent” or“inert diluent” mean a solvent or diluent which is essentially inertunder the conditions of the reaction in which it is employed as asolvent or diluent. Representative examples of materials which may beused as inert solvents or diluents include, by way of illustration,benzene, toluene, acetonitrile, tetrahydrofuran (“THF”),dimethylformamide (“DMF”), chloroform (“CHCl₃”), methylene chloride (ordichloromethane or “CH₂Cl₂), diethyl ether, ethyl acetate, acetone,methylethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable salt” means those salts which retain thebiological effectiveness and properties of the parent compounds andwhich are not biologically or otherwise harmful as the dosageadministered. The compounds of this invention are capable of formingboth acid and base salts by virtue of the presence of amino and carboxylgroups respectively.

Pharmaceutically acceptable base addition salts may be prepared frominorganic and organic bases. Salts derived from inorganic bases include,but are not limited to, the sodium, potassium, lithium, ammonium,calcium, and magnesium salts. Salts derived from organic bases include,but are not limited to, salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines, including isopropylamine, trimethyl amine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine, andN-ethylpiperidine. It should also be understood that other carboxylicacid derivatives would be useful in the practice of this invention, forexample carboxylic acid amides, including carboxamides, lower alkylcarboxamides, di(lower alkyl) carboxamides, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

The compounds of this invention typically contain one or more chiralcenters. Accordingly, this invention is intended to include racemicmixtures, diasteromers, enantiomers and mixture enriched in one or moresteroisomer. The scope of the invention as described and claimedencompasses the racemic forms of the compounds as well as the individualenantiomers and non-racemic mixtures thereof.

The term “treatment” as used herein includes any treatment of acondition or disease in an animal, particularly a mammal, moreparticularly a human, and includes:

(i) preventing the disease or condition from occurring in a subjectwhich may be predisposed to the disease but has not yet been diagnosedas having it;

(ii) inhibiting the disease or condition, i.e. arresting itsdevelopment; relieving the disease or condition, i.e. causing regressionof the condition; or. relieving the conditions caused by the disease,i.e. symptoms of the disease.

The term “disease state which is alleviated by treatment with a broadspectrum antibacterial” as used herein is intended to cover all diseasestates which are generally acknowledged in the art to be usefullytreated with a broad spectrum antibacterial in general, and thosedisease states which have been found to be usefully treated by thespecific antibacterials of this invention. Such disease states include,but are not limited to, treatment of a mammal afflicted with pathogenicbacteria, in particular staphylococci (methicillin sensitive andresistant), streptococci (penicillin sensitive and resistant),enterococci (vancomycin sensitive and resistant), and Clostridiumdifficile

The term “therapeutically effective amount” refers to that amount whichis sufficient to effect treatment, as defined herein, when administeredto a mammal in need of such treatment. The therapeutically effectiveamount will vary depending on the subject and disease state beingtreated, the severity of the affliction and the manner ofadministration, and may be determined routinely by one of ordinary skillin the art.

The term “protecting group” or “blocking group” refers to any groupwhich, when bound to one or more hydroxyl, thiol, amino, carboxyl orother groups of the compounds, prevents undesired reactions fromoccurring at these groups and which protecting group can be removed byconventional chemical or enzymatic steps to reestablish the hydroxyl,thio, amino, carboxyl or other group. The particular removable blockinggroup employed is not critical and preferred removable hydroxyl blockinggroups include conventional substituents such as allyl, benzyl, acetyl,chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl diphenylsilyland any other group that can be introduced chemically onto a hydroxylfunctionality and later selectively removed either by chemical orenzymatic methods in mild conditions compatible with the nature of theproduct. Protecting groups are disclosed in more detail in T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis” 2^(nd) Ed.,1991, John Wiley and Sons, New York.

Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC) and the like,which can be removed by conventional conditions compatible with thenature of the product.

Preferred carboxyl protecting groups include esters such as methyl,ethyl, propyl, t-butyl etc. which can be removed by mild conditionscompatible with the nature of the product.

“Biological effect” as used herein includes, but is not limited to,increased affinity, increased selectivity, increased potency, increasedefficacy, increased duration of action, decreased toxicity, and thelike.

General Synthetic Procedures

The glycopeptide compounds of this invention can be prepared fromreadily available starting materials using the following general methodsand procedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

In the following reaction schemes, the glycopeptide compounds aredepicted in a simplified form as a box “G” that shows the carboxyterminus labeled [C], the vancosamine amino terminus labeled [V], the“non-saccharide” amino terminus (leucine amine moiety) labeled [N], andoptionally, the resorcinol moiety labeled [R] as follows:

In one preferred embodiment, the glycopeptide compounds of the presentinvention are prepared by reductive alkylation of a glycopeptide asshown in the following reaction:

where A represents R^(a) minus one carbon atom and R^(a), R^(b), Y, andZ are as defined herein. This reaction is typically conducted by firstcontacting one equivalent of a glycopeptide, such as vancomycin, with anexcess, preferably from 1.1 to 1.3 equivalents, of the desired aldehydein the presence of an excess, preferably about 2.0 equivalents, of atertiary amine, such as diisopropylethylamine (DIPEA) and the like. Thisreaction is typically conducted in an inert diluent, such as DMF, atambient temperature for about 1 to 2 hours until formation of thecorresponding imine and/or hemiaminal is substantially complete. Theresulting imine and/or hemiaminal is typically not isolated, but isreacted in situ with a metal hydride reducing agent, such as sodiumcyanoborohydride and the like, to afford the corresponding amine. Thisreaction is typically conducted by contacting the imine and/orhemiaminal with about 1 to 1.2 equivalents of the reducing agent atambient temperature in methanol in the presence of an excess, preferablyabout 3 equivalents, of trifluoroacetic acid. The resulting alkylatedproduct is readily purified by conventional procedures, such asreverse-phase HPLC. Surprisingly, by forming the imine and/or hemiaminalin the presence of a trialkyl amine, the selectivity for the reductivealkylation reaction is greatly improved, i.e., reductive alkylation atthe amino group of the saccharide (e.g., vancosamine) is favored overreductive alkylation at the N-terminus (e.g., the leucinyl group) by atleast 10:1, more preferably 20:1.

If desired, the glycopeptide compounds of this invention can also beprepared in a step-wise manner in which a precursor to the—R^(a)—Y—R^(b)—(Z)_(x) group is first attached the glycopeptide byreductive alkylation, followed by subsequent elaboration of the attachedprecursor using conventional reagent and procedures to form the—R^(a)—Y—R^(b)—(Z)_(x) group as illustrated below. Additionally, ketonesmay also be employed in the above-described reductive alkylationreactions to afford α-substituted amines.

Any glycopeptide having an amino group may be employed in thesereductive alkylation reactions. Such glycopeptides are well-known in theart and are either commercially available or may be isolated usingconventional procedures. Suitable glycopeptides are disclosed, by way ofexample, in U.S. Pat. Nos. 3,067,099; 3,338,786; 3,803,306; 3,928,571;3,952,095; 4,029,769; 4,051,237; 4,064,233; 4,122,168; 4,239,751;4,303,646; 4,322,343; 4,378,348; 4,497,802; 4,504,467; 4,542,018;4,547,488; 4,548,925; 4,548,974; 4,552,701; 4,558,008; 4,639,433;4,643,987; 4,661,470; 4,694,069; 4,698,327; 4,782,042; 4,914,187;4,935,238; 4,946,941; 4,994,555; 4,996,148; 5,187,082; 5,192,742;5,312,738; 5,451,570; 5,591,714; 5,721,208; 5,750,509; 5,840,684; and5,843,889; the disclosures of which are incorporated herein by referencein their entirety. Preferably, the glycopeptide employed in the abovereaction is vancomycin.

The aldehydes and ketones employed in the reactive alkylation reactionare also well-known in the art and are either commercially available orcan be prepared by conventional procedures using commercially availablestarting materials and conventional reagents. Typically, such materialsare prepared by conventional coupling of, for example, functionalizedacetals having an amino, thiol, hydroxyl, halo or other substitutent,with an suitable intermediate having a complementary functional group toform sulfides, ethers, amines, sulfonamides and the like. Subsequenthydrolysis of the acetal affords the corresponding aldehyde. Suchreactions are well-known in the art and are described, for example, inMarch, Advanced Organic Chemistry, Fourth Edition, John Wiley & Sons,New York (1992), and references cited therein. Representative synthesisof aldehyde compounds are illustrated in Schemes 1-5:

where R represents —R^(b)—(Z)_(x) or —(R^(b) minus one carbonatom)-(Z)_(x) (where R^(b), Z and x are as defined herein).

By way of further illustration, the following schemes describe thesynthesis of representative starting materials and compounds of thisinvention. For example, Scheme A illustrates a method for preparing anFmoc-aminoaldehyde 5 from the corresponding aminoalcohol 3, where A isas defined herein. In this reaction, the aminoalcohol is protected byconventional techniques, for example, by treatment with9-fluorenylmethyl chloroformate in the presence of base, to yield theFmoc-protected aminoalcohol 4. Oxidation by known techniques thenprovides the aldehyde 5.

Scheme B illustrates an alternate route to F-moc-protected aminoaldehyde5. This route is described in further detail in Sasake, Y., Abe, J.Chem. Pharm. Bull. (1997), 45(1), 13-17.

The Fmoc-protected aminoaldehyde of formula 5 can then be reacted with aglycopeptide, for example vancomycin, as shown in Scheme C.

where B represents —(R^(b) minus one carbon atom)-(Z)_(x), where R^(b),Z and x are as defined herein.

This reaction is conducted under reductive alkylation conditions toyield a glycopeptide intermediate 11. Deprotection of 11 with piperidineyields the corresponding the glycopeptide 12 having a primary aminogroup. Reaction of 12 with aldehyde 13 under standard reductivealkylation conditions gives glycopeptide derivative 14 and thecorresponding bis-adduct 15, which are separated by conventionaltechniques, such as HPLC.

Scheme D illustrates a method for preparing an Fmoc protectedaminoaldehyde 24. In this scheme, reaction of acid chloride 19 withaminoester 20 under conventional amide coupling conditions givesamidoester 21. Reduction of the both the ester and amide moieties usinga metal hydride reducing agent, such as lithium aluminum hydride (LAH)gives aminoalcohol 22. Protection and oxidation, as in Scheme A, yieldsan aldehyde of formula 24.

Alternatively, aldehyde 24 can be prepared as shown in Scheme D′. Inthis reaction, direct alkylation of amino alcohol 3 under conventionalamine alkylation conditions gives amino alcohol 22, which can then beused as described above in Scheme D.

Scheme E illustrates an alternative method for preparing aldehyde 24. Inthis reaction, amino acetal 6 is reductively alkylated to provide 25.Subsequent protection of the amino group and hydrolysis of the acetalunder conventional conditions then provides aldehyde 24.

Scheme F illustrates another method for reductive alkylation of aglycopeptide. In this scheme, Fmoc-protected aldehyde 24, prepared asdescrubed above, is reacted with a glycopeptide 10, such as vancomycin,under reductive alkylation conditions to afford glycopeptide derivative27. Subsequent deprotection with piperidine provides glycopeptidederivative 14.

Scheme G illustrates the conversion of the carboxyl group of aglycopeptide derivative, such as vancomycin, into an amide. In thisreaction, amine 28 is reacted with a glycopeptide derivative, such as27, under standard peptide coupling conditions, for example, PyBOP andHOBT in DMF, to provide amide 29, after deprotection.

Scheme H illustrates the introduction of an aminoalkyl sidechain at theresorcinol moiety of a glycopeptide, such as vancomycin, via a Mannichreaction. In this reaction, amine 30 and an aldehyde, such as formalin(a source of formaldehyde), are reacted with the glycopeptide underbasic conditions to give the glycopeptide derivative 31.

Similarly, Scheme I illustrates a introduction of a substituent of theformula —R^(a)Y—R^(b)—(Z)_(x) at the resorcinol moiety of a glycopeptideusing the Mannich reaction. In these reactions, excess aldehyde, such asformaldehyde, can react to afford the cyclized compounds of formula VIIaand/or VIIb.

Scheme J illustrates a synthesis of a glycopeptide derivative usingseveral of the reactions described above. In this scheme, glycopeptidederivative 27 is derivatized at the resorcinol moiety using the Mannichreaction described in Scheme H to provide glycopeptide derivative 40.Deprotection and amide coupling at the carboxyl group, as described inScheme G, affords glycopeptide derivative 42.

Scheme L illustrates multiple reductive alkylation reaction of aglycopeptide derivative 27 to afford glycopeptide derivative 44a.

Additional details and other methods for preparing the compounds of thisinvention are described in the Examples below.

Pharmaceutical Compositions

This invention also includes pharmaceutical composition containing thenovel glycopeptide compounds of this invention. Accordingly, theglycopeptide compound, preferably in the form of a pharmaceuticallyacceptable salt, can be formulated for oral or parenteral administrationfor the therapeutic or prophylactic treatment of bacterial infections.

By way of illustration, the glycopeptide compound can be admixed withconventional pharmaceutical carriers and excipients and used in the formof tablets, capsules, elixirs, suspensions, syrups, wafers, and thelike. Such pharmaceutical compositions will contain from about 0.1 toabout 90% by weight of the active compound, and more generally fromabout 10 to about 30%. The pharmaceutical compositions may containcommon carriers and excipients, such as corn starch or gelatin, lactose,sucrose, microcrystalline cellulose, kaolin, mannitol, dicalciumphosphate, sodium chloride, and alginic acid. Disintegrators commonlyused in the formulations of this invention include croscarmellose,microcrystalline cellulose, corn starch, sodium starch glycolate andalginic acid.

A liquid composition will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, with a suspendingagent, preservative, surfactant, wetting agent, flavoring or coloringagent. Alternatively, a liquid formulation can be prepared from areconstitutable powder.

For example a powder containing active compound, suspending agent,sucrose and a sweetener can be reconstituted with water to form asuspension; and a syrup can be prepared from a powder containing activeingredient, sucrose and a sweetener.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch and ethylcellulose. Lubricants that canbe used include magnesium stearate or other metallic stearates, stearicacid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

The compounds of the invention and their pharmaceutically acceptablesalts that are active when given parenterally can be formulated forintramuscular, intrathecal, or intravenous administration.

A typical composition for intramuscular or intrathecal administrationwill consist of a suspension or solution of active ingredient in an oil,for example arachis oil or sesame oil. A typical composition forintravenous or intrathecal administration will consist of a sterileisotonic aqueous solution containing, for example active ingredient anddextrose or sodium chloride, or a mixture of dextrose and sodiumchloride. Other examples are lactated Ringer's injection, lactatedRinger's plus dextrose injection, Normosol-M and dextrose, Isolyte E,acylated Ringer's injection, and the like. Optionally, a co-solvent, forexample polyethylene glycol, a chelating agent, for exampleethylenediamine tetracetic acid, and an anti-oxidant, for example,sodium metabisulphite may be included in the formulation. Alternatively,the solution can be freeze dried and then reconstituted with a suitablesolvent just prior to administration.

The compounds of the invention and their pharmaceutically acceptablesalts which are active on rectal administration can be formulated assuppositories. A typical suppository formulation will generally consistof active ingredient with a binding and/or lubricating agent such as agelatin or cocoa butter or other low melting vegetable or synthetic waxor fat.

The compounds of this invention and their pharmaceutically acceptablesalts which are active on topical administration can be formulated astransdermal compositions or transdermal delivery devices (“patches”).Such compositions include, for example, a backing, active compoundreservoir, a control membrane, liner and contact adhesive. Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference in its entirety. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Suitable doses are in the general range of from 0.01-100 mg/kg/day,preferably 0.1-50 mg/kg/day. For an average 70 kg human, this wouldamount to 0.7 mg to 7 g per day, or preferably 7 mg to 3.5 g per day.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

The following formulation examples illustrate representativepharmaceutical compositions of the present invention.

Formulation Example A

This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention:

Ingredients Quantity per tablet, (mg) Active Compound 200 Lactose,spray-dried 148 Magnesium stearate 2

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

Formulation Example B

This example illustrates the preparation of another representativepharmaceutical composition for oral administration of a compound of thisinvention:

Ingredients Quantity per tablet, (mg) Active Compound 400 Cornstarch 50Lactose 145 Magnesium stearate 5

The above ingredients are mixed intimately and pressed into singlescored tablets.

Formulation Example C

This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention.

An oral suspension is prepared having the following composition.

Ingredients Active Compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0g Methyl paraben 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 mL

Formulation Example D

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

An injectable preparation buffered to a pH of 4 is prepared having thefollowing composition:

Ingredients Active Compound 0.2 g Sodium Acetate Buffer Solution (0.4 M)2.0 mL HCl (1N) q.s. to pH 4 Water (distilled, sterile) q.s. to 20 mL

Formulation Example E

This example illustrates the preparation of a representativepharmaceutical composition for injection of a compound of thisinvention.

A reconstituted solution is prepared by adding 20 mL of sterile water to1 g of the compound of this invention. Before use, the solution is thendiluted with 200 mL of an intravenous fluid that is compatible with theactive compound. Such fluids are chosen from 5% dextrose solution, 0.9%sodium chloride, or a mixture of 5% dextrose and 0.9% sodium chloride.Other examples are lactated Ringer's injection, lactated Ringer's plus5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, andacylated Ringer's injection.

Formulation Example F

This example illustrates the preparation of a representativepharmaceutical composition for topical application of a compound of thisinvention.

Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineraloil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA(butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

Formulation Example G

This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

A suppository totaling 2.5 grams is prepared having the followingcomposition:

Ingredients Active Compound 500 mg Witepsol H-15* balance(*triglycerides of saturated vegetable fatty acid; a product ofRiches-Nelson, Inc., New York, N.Y.)Utility

The glycopeptide compounds of this invention, and their pharmaceuticallyacceptable salts, are useful in medical treatments and exhibitbiological activity, including antibacterial activity, which can bedemonstrated in the tests described in the Examples. Such tests are wellknown to those skilled in the art, and are referenced and described inLorian “Antibiotics in Laboratory Medicine”, Fourth Edition, Williamsand Wilkins (1991), which is hereby incorporated by reference.

Accordingly, this invention provides methods for treating infectiousdiseases, especially those caused by Gram-positive microorganisms, inanimals. The compounds of this invention are particularly useful intreating infections caused by methicillin-resistant staphylococci. Also,the compounds are useful in treating infection due to enterococci,including vancomycin-resistant enterococci (VRE). Examples of suchdiseases are severe staphylococcal infections, for example,staphylococcal endocarditis and staphylococcal septicemia. The animalmay be either susceptible to, or infected with, the microorganism. Themethod comprises administering to the animal an amount of a compound ofthis invention which is effective for this purpose. In general, aneffective amount of a compound of this invention is a dose between about0.5 and about 100 mg/kg. A preferred dose is from about 1 to about 60mg/kg of active compound. A typical daily dose for an adult human isfrom about 50 mg to about 5 g.

In practicing this method, the antibiotic can be administered in asingle daily dose or in multiple doses per day. The treatment regimenmay require administration over extended periods of time, for example,for several days or for from one to six weeks. The amount peradministered dose or the total amount administered will depend on suchfactors as the nature and severity of the infection, the age and generalhealth of the patient, the tolerance of the patient to the antibioticand the microorganism or microorganisms in the infection.

Among other properties, the compounds of this invention have also beenfound to be more chemically stable compared to N-acyl glycopeptidederivatives. More specifically, it has been observed that acylation ofthe amino group of the vancosamine moiety of vancomycin increases therate of hydrolysis of the disaccharide moiety. In contrast, when thecompounds of this invention are substituted on the amino group of thevancosamine moiety of vancomycin with a —R^(a)—Y—R^(b)—(Z)_(x) group, noincrease in the rate of hydrolysis of the disaccharide moiety isobserved.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. Any abbreviations not defined have their generally acceptedmeaning. Unless otherwise stated, all temperatures are in degreesCelsius.

BOC, Boc = tert-butoxycarbonyl DIBAL-H = diisobutylaluminum hydrideDIPEA = diisopropylethylamine DMF = N,N-dimethylformamide DMSO =dimethyl sulfoxide eq. = equivalent Et = ethyl EtOAc = ethyl acetateFmoc = 9-fluorenylmethoxycarbonyl HOBT = 1-hydroxybenzotriazole hydrateMe = methyl PyBOP = benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate TEMPO = 2,2,6,6-tetramethyl-piperidinyloxy, freeradical TFA = trifluoroacetic acid THF = tetrahydrofuran TLC, tlc = thinlayer chromatography

In the following example, vancomycin hydrochloride semi-hydrate waspurchased from Alpharma, Inc. Fort Lee, N.J. 07024 (Alpharma AS, OsloNorway). Other reagents and reactants are available from AldrichChemical Co., Milwaukee, Wis. 53201.

General Procedure A Reductive Alkylation of Vancomycin

To a mixture of vancomycin (1 eq.) and the desired aldehyde (1.3 eq.) inDMF was added DIPEA (2 eq.). The reaction was stirred at ambienttemperature for 1-2 hours and monitored by reverse-phase HPLC. Methanoland NaCNBH₃ (1 eq.) were added to the solution, followed by TFA (3 eq.).Stirring was continued for an additional hour at ambient temperature.After the reaction was complete, the methanol was removed in vacuo. Theresidue was precipitated in acetonitrile. Filtration gave the crudeproduct which was then purified by reverse-phase HPLC. If desired, otherglycopeptides may be used in this procedure.

General Procedure B Aglycon Alkylation Procedure I

A white suspension of vancomycin aglycon TFA salt (1.0 eq.), Cs₂CO₃ (3.5eq.) in DMF is stirred at room temperature for 30 min. An alkyl halide(1.1 eq.) is added. The reaction mixture is then stirred for 5-24 hbefore quenching with acetic acid. The resulting brownish solution isdripped into water to give a white precipitate. Filtration affords thecrude monoalkylated product which can be purified by reverse-phase HPLCif desired.

General Procedure C Aglycon Alkylation Procedure II

Under nitrogen, the trifluoroacetate salt of vancomycin aglycone (1 eq)is dissolved in DMF and stirred vigorously at room temperature withpotassium carbonate (8-10 eq) for an hour. An alkyl halide (1 eq) isadded and the mixture is stirred vigorously overnight. The crude productis collected by precipitation into diethyl ether, washed withacetonitrile and taken up in 10% aqueous acetic acid. The mono-alkylatedproduct is obtained upon reverse-phase HPLC purification.

General Procedure D Preparation of Amino-Substituted Aldehydes

A solution of an aminoacetal (1 eq), such as 2-aminoacetaldehydedimethyl acetal, an aldehyde (1.05 eq), and NaCNBH₃ (1 eq) in CH₂Cl₂ isstirred at room temperature for 1-4 hours. The reaction is monitored byTLC. To the reaction mixture are added FmocCl(1 eq) and DIPEA (2 eq) at0° C. Stirring is continued for 1-2 hours at room temperature. Thereaction is then washed with 0.1 N HCl, water and brine. The solvent isremoved in vacuo and the residue is purified by flash chromatographygave the amino-substituted acetal.

To the solution of above amino-substituted acetal in acetone is added 6N HCl (1.5 eq). The reaction is stirred at room temperature for 5-16hours. Solvent is removed in vacuo and the residue is dried under highvacuum to give crude amino-substituted aldehyde which is typically usedwithout further purification.

General Procedure E Preparation of Thio-Substituted Aldehydes

A solution of a bromoacetal (1 eq), such as dimethyl2-bromoacetaldehyde, and sodium iodide (1 eq) in DMF is stirred atambient temperature for 0.5 h. To the solution is added a substitutedthiol (1 eq), such as n-decyl thiol, followed by potasium carbonate (1eq). The mixture is stirred at 25-80° C. for 4-16 hours. The reaction isthen taken up with ethyl acetate, washed twice with water and once withsat. NaCl. The organic layer is dried over MgSO₄ and the solvent isremoved in vacuo. Purification on flash chromatography (hexan:ethylacetate=8:1) provides the corresponding thio-substituted acetal.

To a solution of the thio-substituted acetal in acetone was added 6 NHCl (1.5 eq). The reaction is stirred at room temperature for 5-16hours. The solvent is removed in vacuo and the residue is dried underhigh vacuum to give crude thio-substituted aldehyde which is typicallyused without further purification.

General Procedure F Preparation of Thio-Substituted Aldehydes

A mixture of a thiol ester (1 eq), such as methyl thioglycolate, sodiumiodide (1 eq), an alkyl bromide (1 eq) and potasium carbonate (1 eq) inDMF is stirred at room temperature for 4-16 hours. The reaction is takenup with ethyl acetate and washed with water and brine. The organic layeris dried over magnesium sulfate and solvent is removed in vacuo.Purification on flash chromatography provides the thio-substitutedester.

The thio-substituted ester in dry ether is treated with DIBAL-H (1 Msolution in cyclohexane, 1.3 eq) at −78° C. The reaction is then stirredat −78° C. for 2-4 hours. TLC is used to monitor the reaction progress.Upon completion, ethyl formate (0.5 eq) is added to quench the reaction.The reaction is then washed with 10% acetic acid, water and brine. Theorganic layer is dried over magnesium sulfate and the solvent removed toafford the crude thio-substituted aldehyde which is typically usedwithout further purification.

General Procedure G Preparation of Alkoxy-Substituted Aldehydes

A solution of a hydroxyacetal (1 eq), such as dimethyl2-hydroxyacetaldehyde, in THF is treated with sodium hydride (1 eq) at0° C. After hydrogen evolution ceases, an alkyl bromide is added at 0°C. The reaction is then stirred at room temperature for 1-4 hours. Thereaction is taken up with ethyl acetate and washed with water and brine.The solvent is removed in vacuo and the residue typically purified byflash chromatography to afford the alkoxy-substituted acetal.

To a solution of the alkoxy-substituted acetal in acetone is added 6 NHCl (1.5 eq). The reaction is stirred at room temperature for 5-16hours. The solvent is removed in vacuo and the residue is dried underhigh vacuum to give crude alkoxy-substituted aldehyde which is typicallyused without further purification.

General Procedure H Preparation of Sulfonamido-Substituted Aldehydes

A solution of an aminoacetal (1 eq), such as dimethyl2-aminoacetaldehyde, and diiospropylethylamine (2 eq) in THF is treatedwith a sulfonyl chloride (1 eq) at 0° C. The reaction is then stirred atroom temperature for 1-4 hours. The reaction is then taken up with ethylacetate and washed with 0.1 N HCl, water and brine. The solvent isremoved in vacuo and the residue purified by flash chromatography gavethe sulfonamido-substituted acetal.

To a solution of the sulfonamido-substituented acetal in acetone isadded 6 N HCl (1.5 eq). The reaction is stirred at room temperature for5-16 hours. The solvent is then removed in vacuo and the residue isdried under high vacuum to give crude sulfonamido-substituted aldehydewhich is typically used without further purification.

Example A Preparation of Fmoc-Aminoacetaldehyde

Fmoc-protected aminoethanol was prepared from aminoethanol byconventional techniques (e.g., as described in Examples B and C below).

To a mixture of Fmoc-aminoethanol (37.64 g, 133 mmol, 1.0 equiv), TEMPO(0.008 M in CH₂Cl₂, 332.5 mL, 2.66 mmol, 0.02 equiv), KBr (0.5 M inwater, 53.2 mL, 26.6 mmol, 0.2 equiv) and ethyl acetate (1,500 mL), at0° C., was added NaOCl (0.35 M, buffered to pH 8.6 by NaHCO₃, 760 mL,266 mmol, 2.0 equiv). A mechanical stir was used to ensure efficientstirring, and the reaction was monitored by TLC. After 20 min, the twolayers were separated. The aqueous layer was extracted with ethylacetate (2×250 mL), the combined organic layers were washed withsaturated Na₂S₂O₃, water, and brine, dried over Na₂SO₄, filtered andconcentrated to about 400 mL. Hexane (1,600 mL) was added to give awhite precipitate. After filtration, Fmoc-aminoacetaldehyde (25.2 g,67%) was collected as a white powder.

Example B Preparation of N-Fmoc-2-(n-Decylamino)acetaldehyde

To a solution of n-decanoyl chloride (2.7 mL, 13 mmol, 1.0 eq) inmethylene chloride (20 mL) in an ice/acetone bath was added a mixture ofglycine methyl ester hydrochloride (2.0 g, 16 mmol, 1.2 eq) and DIPEA(5.1 mL, 29 mmol, 2.2 eq) in methylene chloride (20 mL) dropwise. Thereaction was stirred a further 60 min after complete addition, thenwashed with 3N hydrochloric acid (50 mL) twice, followed by saturatedsodium bicarbonate (50 mL). The organics were dried over magnesiumsulfate and the solvents removed under reduced pressure. Methyl2-Decylamidoacetate (3.0 g, 12 mmol, 95%) was obtained which was used inthe next step without further purification.

Under nitrogen, methyl 2-(n-decylamido)acetate (3.0 g, 12 mmol, 1.0 eq)was dissolved in anhydrous tetrahydrofuran (25 mL) and cooled in an icebath. A solution of lithium aluminum hydride (1 N, 25 mL, 25 mmol, 2.0eq) was added carefully. The resulting solution was refluxed undernitrogen overnight, then cooled in an ice bath. Tetrahydrofuran (50 mL)was added followed by slow addition of sodium sulfate decahydrate untileffervescence ceased. The mixture was allowed to warm to roomtemperature, filtered, then concentrated under vacuum.2-(n-Decylamino)ethanol (2.3 g, 11 mmol, 93%) was obtained which wasused without further purification.

2-(n-Decylamino)ethanol (2.3 g, 11 mmol, 1.1 eq) and DIPEA (2.0 mL, 11mmol, 1.1 eq) were dissolved in methylene chloride (15 mL) and cooled inan ice bath. 9-Fluorenylmethyl chloroformate (2.6 g, 10 mmol, 1.0 eq) inmethylene chloride (15 mL) was added, the mixture stirred for 30 minutesthen washed with 3N hydrochloric acid (50 mL) twice and saturated sodiumbicarbonate (50 mL). The organics were dried over magnesium sulfate, andthe solvents removed under reduced pressure.N-Fmoc-2-(decylamino)ethanol (4.6 g, 11 mmol, 108%) was used withoutfurther purification.

N-Fmoc-2-(n-Decylamino)ethanol (4.6 g, 11 mmol, 1.0 eq) and DIPEA (7.6mL, 44 mmol, 4.0 eq) were dissolved in methylene chloride (30 mL) andcooled in an ice/acetone bath. A solution of sulfur trioxide pyridinecomplex (6.9 g, 43 mmol, 4.0 eq) in dimethyl sulfoxide (30 mL) wasadded, and the solution stirred for 20 minutes. Crushed ice was addedand the mixture partitioned. The organics were washed with 3Nhydrochloric acid twice, saturated sodium bicarbonate and saturatedsodium chloride, dried over magnesium chloride, and concentrated undervacuum. N-Fmoc-2-(n-Decylamino)acetaldehyde (3.4 g, 8 mmol, 74%) wasused without further purification (see example 5).

Example C Preparation of 2-(Decylamino)ethanol

A solution of aminoethanol (30.5 g, 500 mmol, 30.1 mL) and 1-bromodecane(27.65 g, 125 mmol, 26 mL) in ethanol was stirred at 65° C. for 4 hr.The solvent was removed under reduced pressure. The residue was dilutedwith EtOAc (800 mL) and the organic solution was washed with H₂O (2×200mL); saturated aqueous NaHCO₃ (200 mL) and saturated brine (200 mL). Theorganic phase was dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The resulting crude product, 2-(decylamino)ethanol,was used without further purification.

Example D Preparation of N-Fmoc-2-(trans-Dec-4-en-1-ylamino)acetaldehyde

trans-4-Decenal (7.2 g, 46.6 mmol) was mixed with 40 mL (0.37 moL) ofaminoacetaldehyde dimethylacetal in 400 mL of methanol and stirred atroom temperature for 30 minutes. NaCNBH₃ (2.9 g, 46.6 mmol) was added,the reaction was cooled in an ice bath, and 27 mL (0.35 moL) of TFA wasadded dropwise over 5 minutes. The ice bath was then removed and thereaction was stirred for 70 minutes at room temperature, concentrated toa third of its volume, and partitioned between ethyl acetate (250 mL)and 1N NaOH (200 mL). The organic layer was washed with water (3×75 mL),dried over MgSO4 , filtered and concentrated under reduced pressure toyield 11.1 g (45.6 mmol) of 2-(trans-dec-4-en-1-ylamino)acetaldehydedimethyl acetal as a yellow oil that was used directly in the next step.

2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (10.5 g, 43.2mmol) was mixed with dichloromethane (300 mL) and 7.5 mL (43.2 mmol)diisopropylethyl amine and 11.2 g (43.2 mmol) of FMOC-Cl was addedportionwise. The reaction was stirred at room temperature for 3 hoursand then poured into a solution of 10% KHSO₄ (200 mL). The organic layerwas washed with water (200 mL), dried over MgSO₄, and concentrated underreduced pressure. The resulting oil was chromatographed on silica gel in10% EtOAc/Hexanes to give 16.1 g (34.6 mmol) ofN-Fmoc-2-(trans-dec-4-en-1-ylamino)acetaldehyde dimethyl acetal as aclear oil that was used directly in the next step.

N-Fmoc-2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (5 g,10.7 mmol) was mixed with 30 mL of TFA and stirred at room temperaturefor 30 minutes. The reaction was poured into water (140 mL) andcentrifuged to obtain a clear oil. The supernatant was decanted and theoil was mixed with 40 mL of water and centrifuged again. The supernatantwas again decanted and the oil was dissolved in dichloromethane (100mL), dried over MgSO4, filtered, and concentrated under reduced pressureto obtain 5.2 g (12.3 mmol) ofN-Fmoc-2-(trans-Dec-4-en-1-ylamino)acetaldehyde as a clear oil.

Example E Preparation of a Compound of Formula V (where R²² is OH andR²³ is —CH₂—N—(N—CH₃—D-glucamine))

Vancomycin (9.0 g, 5.16 mmol) was added to a solution ofN-methyl-D-glucamine (5.03 g, 25.8 mmol) and 37% formaldehyde (0.43 mL,5.4 mmol) in 50% aqueous acetonitrile (60 mL) under nitrogen and stirredat room temperature. After 4 hours, the acetonitrile was removed invacuo, water (30 mL) was added, and the pH was adjusted to ˜4 with 10%trifluoroacetic acid. The solution was purified by reverse-phase HPLC.Fractions containing the desired product were identified by massspectrometry, pooled, and lyophilized to give the title compound as awhite powder. This intermediate may be further derivatized using theprocedures described herein.

Example F Preparation of a Compound of Formula IV (where R¹⁵ and R¹⁶ areH, R²² is OH and R²⁷ is —CH₂CH₂—NH-Fmoc)

Vancomycin hydrochloride (4.00 g, 2.60 mmol) was suspended in 40 mL of1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone and heated to 70° C.for 15 minutes. N-(9-fluorenylmethoxycarbonyl)aminoacetaldehyde (720 mg,2.6 mmol) was added and the mixture was heated at 70° C. for one hour.Sodium cyanoborohydride (160 mg, 2.5 mmol) in 2 mL methanol was addedand the mixture was heated at 70° C. for 2 hours, then cooled to roomtemperature. The reaction solution was added dropwise to 20 mL ofacetonitrile, giving a precipitate that was collected by centrifugation.The precipitate was purified by reverse-phase HPLC on a Ranin C18Dynamax column (2.5 cm×25 cm, 8 μm particle size), at 10 mL/min flowrate using 0.045% TFA in water as buffer A and 0.045% TFA inacetonitrile as buffer B (HPLC gradient of 10-70% B over 90 minutes),which yielded the title intermediate as its trifluroacetate salt. MScalculated: MH⁺, 1715; Found, 1715.

This compound can be deprotected and further derivatized, forexample,via reductive alkylation, as described herein.

Example G Preparation of an O-Ethyl Aglycone Derivative

Vancomycin hydrochloride hydrate (10 g, 6.4 mmol) was dissolved in 100mL of dimethyl sulfoxide (DMSO) and 3-(dimethylamino)propylamine (3.2mL, 26 mmol) was added. PyBOP (3.3 g, 6.4 mmol) and1-hydroxybenzotriazole (HOBT, 0.9 g, 6.4 mmol) dissolved in 100 mLN,N-dimethylformamide (DMF) was added dropwise at room temperature. Thereaction was stirred for one hour and dripped into acetonitrile to givea white precipitate, which was filtered and washed with acetonitrile,ether and dried under vacuum to give a syrup of crude vancomycin3-(dimethylamino)propyl amide.

A portion of this syrup was dissolved in 100 mL trifluoroacetic acid(TFA), heated at 323 K. for 2 hours, cooled to room temperature andadded dropwise to ether, resulting in a green precipitate. Theprecipitate was collected by filtration, dried under vacuum and purifiedby reverse-phase HPLC (2-50% acetonitrile in water containing 0.1% TFA)to give vancomycin 3-(dimethylamino)propyl amide aglycone, as its TFAsalt.

The aglycone, as its trifluoroacetate salt (500 mg, 340 umol) wasdissolved in 5 mL DMF and potassium carbonate (500 mg, 3.6 mmol) wasadded. The mixture was stirred for 15 minutes at room temperature thentert-butyl N-(2-bromoethyl)carbamate (77 mg, 340 umol) was added. Themixture was stirred at room temperature for 24 hours, then additionaltert-butyl N-(2-bromoethyl)carbamate (70 mg, 310 umol) was added. Themixture was stirred at room temperature for 7 hours then dripped intoether giving a precipitate that was collected by centrifugation, washedwith acetonitrile and dissolved in 5:1:2 water/acetic acid/acetonitrile.This solution was purified by reverse-phase HPLC giving vancomycin3-(dimethylamino)propyl amide O-2-(N-t-BOC-amino)ethoxy aglycone as thetrifluoroacetate salt, which was treated with 1 mL TFA for 30 minutes atroom temperature. Reverse-phase HPLC purification yielded vancomycin3-(dimethylamino)propyl amide O-(2-aminoethyl) aglycone as thetrifluoroacetate salt. This compound can be deprotected and furtherderivatized, for example, via reductive alkylation, as described above.

Example 1 Synthesis of a Compound of Formula III (Where R¹⁵ is—CH₂CH₂—NH—(CH₂)₉CH₃, R¹⁷ is H and R²² is OH)

To an oven-dried, 1000 mL round bottomed flask, equipped with magneticstirring bar, were added vancomycin (34.1 g, 23 mmol, 1 eq),N-Fmoc-aminoacetaldehyde (6.5 g, 23 mmol, 1 eq), DIPEA (8.5 mL, 46 mmol,2 eq) and DMF (340 mL). The mixture was stirred at ambient temperatureover 2 hours, and monitored by HPLC. The reaction became homogenous, and˜90% conversion to the imine was observed. Methanol (340 mL) and NaCNBH₃(4.3 g, 69 mmol, 3 eq) were added to the solution, followed by TFA (5.2mL, 69 mmol, 3 eq). Stirring was continued for an additional hour atambient temperature. After the reaction was complete, methanol wasremoved in vacuo. The residue containing the crude product and DMF wasslowly poured into a 5 L flask and stirred with acetonitrile (3.5 L). Awhite precipitate was formed. The suspension was allowed to settle atambient temperature and the supernetant was decanted. The white solidwas filtered and triturated with ether (2 L). After filtration, thecrude product was dried under high vacuum overnight.

An 8×26 cm column was packed with octadecyl bonded silical gel. Thecolumn was washed with 800 mL of 90% Solvent B [acetonitrile in water,0.1% TFA] and equilibrated with 800 mL of 10% Solvent B. Crude product(10 g) was dissolved in 30% Solvent B (150 mL, containing 2 mL of 3 NHCl) and loaded onto the column. It was then flashed with 10% B (800mL×2), 40% B (800 mL×3) and 90% B (800 mL). The fractions were checkedby analytical HPLC. After lyophilization, N^(van)-Fmoc-aminoethylvancomycin was obtained as its TFA salt.

N^(van)-Fmoc-aminoethyl vancomycin was deprotected to giveN^(van)-aminoethyl vancomycin tri-TFA salt using conventional procedures(e.g. as described in Examples 2 and 3).

To a solution of N^(van)-aminoethyl vancomycin tri-TFA salt (15.5 mg,8.4 micromol) in methanol:DMF:THF (2:1:1, 1.6 mL) was added decanal (92microL, 59 micromol) and sodium cyanoborohydride (0.1M in methanol, 45microl, 4.5 micromol). After 45 minutes, the solvents were removed invacuo, and the residue purified by preperative HPLC. The appropriatefractions were combined and lyophylized to giveN^(van-)2-(n-decylamino)ethyl vancomycin (2.4 mg) as a white powder.Also isolated was N^(van),N^(van)-bis-2-(n-decylamino)ethyl vancomycin(2.9 mg).

Example 2 Synthesis of a Compound of Formula III (Where R¹⁵ is—CH₂CH₂—NH—(CH₂)₉CH₃, R¹⁷ is H and R²² is OH)

Vancomycin hydrochloride (12 g, 7.7 mmol, 1.0 eq),N-Fmoc-2-(n-decylamino)acetaldehyde (3.2 g, 7.6 mmol, 1.0 eq) and DIPEA(2.6 mL, 14.9 mmol, 2.0 eq) were stirred at room temperature in DMF (120mL) for 90 minutes. Sodium cyanoborohydride (1.4 g, 22 mmol, 3.0 eq) wasadded, followed by methanol (120 mL) then trifluoroacetic acid (1.8 mL,23 mmol, 3.0 eq). The mixture was stirred for 60 minutes at roomtemperature, then the methanol removed under reduced pressure. Theresulting solution was added to 600 mL diethyl ether giving aprecipitate which was filtered, washed with ether, and dried undervacuum. The crude product was purified on a reverse-phase flash column,eluting with 10, 20, 30% acetonitrile in water (containing 0.1%trifluoroacetic acid) to remove polar impurities (such as residualvancomycin) then the product was eluted with 70% acetonitrile in water(containing 0.1% trifluoroacetic acid) to give 9 g ofN^(van)-(N-Fmoc-2-n-decylaminoethyl)vancomycin as its trifluoroacetatesalt (4.3 mmol, 56%).

N^(van)-(N-Fmoc-2-n-decylaminoethyl)vancomycin (100 mg) was dissolved in1 mL DMF (1 mL) and treated with piperidine (200 uL) for 30 minutes. Themixture was precipitated into ether, centrifuged and washed withacetonitrile. Reverse-phase preparative HPLC (10-70% acetonitrile inwater containing 0.1% trifluoroacetic acid over 120 minutes) gaveN^(van-2)-(n-decylamino)ethyl vancomycin as its TFA salt.

Example 3 Synthesis of a Compound of Formula III (Where R¹⁵ is—CH₂CH₂—NH—(CH₂)₉CH₃, R¹⁷ is H and R²² is —N—(D-glucosamine)

N^(van)-(N-Fmoc-2-n-decylaminoethyl)vancomycin (100 mg, 48 umol, 1.0 eq)was dissolved in 1 mL DMF and glucosamine hydrochloride was added (31mg, 144 umol, 3.0 eq). The mixture was stirred vigorously for 30 minutes(the glucosamine hydrochloride did not fully dissolve), DIPEA (60 uL,344 umol, 7.2 eq) was added and the mixture stirred vigorously for afurther 30 minutes. A solution ofbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP, 50 mg, 96 umol, 2.0 eq) and 1-hydroxybenzotriazole (14 mg, 104umol, 2.2 eq) in 500 uL DMF was prepared. The PyBOP solution was addedin 5 batches of 60 uL at intervals of 5 minutes to the vigorouslystirred suspension of the other reaction components. The reaction wasstirred an additional 30 minutes then precipitated into acetonitrile.The solid was collected by centrifugation, taken up in 1 mLN,N-dimethylformamide and treated with 200 uL piperidine for 30 minutes.Precipitation into ether was followed by centrifugation and the solidwashed with acetonitrile. Reverse-phase preparative HPLC (10-70%acetonitrile in water containing 0.1% trifluoroacetic acid over 120minutes) gave a compound of formula III where R¹⁵ is—CH₂CH₂—NH—(CH₂)₉CH₃ and R²² is —N—(D-glucosamine as itstrifluoroacetate salt.

Example 4 Synthesis of a Compound of Formula III (Where R¹⁵ is—CH₂CH₂—NH—(CH₂)₉CH₃ and R²² is —NH—CH(COOH)CH₂COOH)

HOBt (1.47 g, 10.9 mmol), PyBOP (7.57 g, 14.6 mmol), and thebis-fluorenylmethyl ester of L-aspartic acid (TFA, 6.26 g, 10.4 mmol)were added to a well stirred solution ofN^(van)-(N-Fmoc-2-n-decylaminoethyl)vancomycin (20 g, 10.4 mmol) andDIPEA (5.44 mL, 31.2 mmol) in DMF (440 mL). The reaction was completeafter 1 hr by MS. The mixture was precipitated into CH₃CN (4 L) andcentrifuged. The supernatant was decanted and the pellet redissolved inDMF (440 mL). Piperidine (44 mL) was added and the reaction monitored byMS. After 1 hr reaction was complete. Precipitate via dropwise additionto Et₂O (4 L) with continued stirring overnight. The solid was collectedvia filtration and dried in vacuo. The resulting solid was thentriturated with CH₃CN and collected via filtration and dried in vacuogiving desired product as an off-white solid which was purified byreverse phase HPLC.

Example 5 Synthesis of a Compound of Formula V (Where R¹⁵ is H and R²³is —CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃)

To 50% aqueous acetonitrile (1.0 mL) was added diaminoethane (30 mg, 0.5mmol), 37% formalin (7.6 uL, 0.20 mmol) and vancomycin hydrochloride(140 mg, 0.10 mmol). After stirring for 3 h, the product wasprecipitated by the addition of acetonitrile (12 mL). The solid wasisolated by centrifugation, then washed with ether (12 mL). Theresulting solid was dried in vacuo, and purified by reverse-phase HPLC(5-15% B over 40 min at a flow rate of 50 ml/min). Fractions containingthe desired product were identified by mass spectrometry, pooled, andlyophilized to give a compound of formula V where R²³ is—CH₂—NH—CH₂CH₂NH₂ (85 mg) as a white powder. MS calculated (MH+), 1520;found, 1520.

To a solution of the compound from the above step (80 mg, 0.040 mmol) inethanol (1.0 mL) and DMF (1.0 mL) was added n-decanal (6.3 mg, 0.040mmol), and the mixture was stirred for 45 minutes. Sodiumcyanoborohydride (0.1M in methanol, 400 uL, 0.040 mmol) was then addedand the mixture stirred for 3 hours. The solvents were removed in vacuo,and the residue purified by preparative HPLC. Fractions containing thedesired product were identified by mass spectrometry, pooled, andlyophilized to the title compound as a white powder. MS calculated(MH+), 1661; found, 1661.

Example 6 Synthesis of a Compound of Formula V (Where R¹⁵ is—CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃ R²² is -N-(D-glucosamine) and R²³ is—CH₂—N—(N—CH₃-D-glucamine))

To 50% aqueous acetonitrile (10 mL) was added sequentiallyN-methyl-D-glucamine (975 mg, 5.0 mmol), 37% formalin (84 uL, 1.1 mmol),DIPEA (348 uL, 2.0 mmol) and N^(van)-(N-Fmoc-2-n-decylaminoethyl)vancomycin (2.15 g, 1.030 mmol). After stirring for 16 h, the productwas precipitated by the addition of acetonitrile (80 mL). The solid wasisolated by centrifugation, then washed with acetonitrile (80 mL). Thesolid was dissolved in DMF (6.0 mL) and piperidine (2.0 mL). After 30minutes, the product was precipitated by the addition of acetonitrile(80 mL). The solid was isolated by centrifugation, then washed withether (80 mL). The resulting solid was dried in vacuo, and purified byreverse-phase HPLC (10-35% B) over 40 min at a flow rate of 50 mL/min).Fractions containing the desired product were identified by massspectrometry, pooled, and lyophilized to give a compound of formula Vwhere R¹⁵ is —CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃ and R²³ is—CH₂—N—(N—CH₃-D-glucamine (1.34 g) as a white powder. MS calculated(MH+), 1839; found, 1839.

The above compound (tetra TFA salt) (150 mg, 0.065 mmol) was dissolvedin DMF. To this solution was added sequentially D-glucosaminehydrochloride (35 mg, 0.16 mmol ), DIPEA (65 uL, 0.32 mmol), and asolution of PyBOP and HOBt in DMF (3.85 mL of a solution 0.02 M in each,0.077 mmol each). After 30 minutes, the product was precipated by theaddition of acetonitrile (40 mL). The solid was isolated bycentrifugation, then washed with acetonitrile (40 mL). The resultingsolid was dried in vacuo, and purified by reverse-phase HPLC (10-35% Bover 40 min at a flow rate of 50 mL/min). Fractions containing thedesired product were identified by mass spectrometry, pooled, andlyophilized to the title compound as a white powder. MS calculated(MH+), 2000; found, 2000.

Example 7 Synthesis of a Compound of Formula IV (Where R¹⁵ is—CH₂—NH—CH₂CH₂—NH—(CH₂)₉CH₃ R²² is —OH and R²⁷ is —CH₂C(O)OCH₂CH₃)

A solution of vancomycin monohydrochloride (3.72 g, 2.5 mmol) in DMF (35mL) was treated with diisopropylethylamine (0.87 mL, 5.0 mmol) followedby N-Fmoc-n-decylaminoacetaldehyde (1.05 g, 2.5 mmol). The resultingreaction mixture was stirred at room temperature for 12 hours. Ethylglyoxylate (2.5 mmol, 50% solution in toluene) was added and thereaction solution was stirred at 50° C. for 6 hours. The reactionmixture was cooled to room temperature and was treated with NaCNBH₃(0.376 g, 6.0 mmol) followed by a solution of TFA (0.58 mL, 7.5 mmol) inMeOH (35 mL). After 20 min, MeOH was removed under reduced pressure andthe crude was precipitated in acetonitrile (400 mL). The solid wascollected by filtration. The crude was purified by preparative HPLC togive title compound. MS(M+H) 1939.2(M+, calculated 1938.7).

Example 8 Synthesis of a Compound of Formula IV (Where R¹⁵ is—CH₂—C(O)OCH₃ R²² is —OH and R²⁷ is —CH₂C(O)OCH₃)

A solution of vancomycin hydrochloride (7.43 g, 5.0 mmol) in DMSO (100mL) was treated with diisopropylethylamine (1.74 mL, 10.0 mmol) followedby methyl bromoacetate (0.842 g, 5.5 mmol) at room temperature. Thereaction mixture was stirred at room temperature overnight. The crudeproduct was precipitated using acetonitrile (1000 mL). The crude productwas collected and purified by preparative HPLC to provide the titleproduct. MS(M+H) 1522.0(M+, calculated 1519.45).

Example 9 Synthesis of a Compound of Formula VIII (Where R¹⁹ is—CH₂—C(O)OC(CH₃)₃)

Under nitrogen, the trifluoroacetate salt of vancomycin aglycone (385mg, 310 umol) was dissolved in N,N-dimethylformamide (4 mL). Potassiumcarbonate (400 mg, 2.9 mmol) was added and the mixture was stirredvigorously at room temperature with for 55 minutes. tert-Butylchloroacetate (44 uL, 310 umol) was then added and the mixture stirredvigorously overnight. The crude reaction mixture was precipitated intodiethyl ether (40 mL) and the solids were collected by centrifugation,washed with acetonitrile (40 mL) and taken up in 10% acqueous aceticacid. The title compound was obtained upon reverse-phase HPLCpurification (calculated mass: 1256.4, observed (M+H): 1257.7).

Example 10 Synthesis of a Compound of Formula VIII (Where R¹⁹ is—CH₂CH₂CH₂—NH—(CH₂)₉CH₃)

A white suspension of vancomycin aglycon TFA salt (2.0 g, 1.59 mmol, 1.0eq) Cs₂CO₃ (1.81 g, 5.56 mmol, 3.5 eq) and DMF (34.0 mL) was stirred atroom temperature for 30 min. Then t-butyl N-(3-iodopropyl)carbamate(0.54 g, 1.9 mmol, 1.2 eq) was added. The reaction mixture was stirredfor 24 h before quenching with acetic acid. The resulting brownishsolution was dripped into water to give a white precipitate. Vacuumfiltration gave 1.5 g a white crystalline solid which was used for nextstep without further purification.

To a mixture of the above compound (1.05 g, 0.75 mmol, 1.0 eq), DIPEA(0.65 mL, 3.75 mmol, 5.0 eq) and DMF (10 mL), was added Fmoc-Cl (0.19 g,0.75 mmol, 1.05 eq) in portions. After stirring at room temperature for4 h, TFA (0.6 mL) was added to quench the reaction. Then the reactionmixture was dripped into 500 mL of water to give a white precipitate.Filtration gave 1.1 g of a white crystalline solid which was used fornext step without further purification.

The above compound (1.17 g) was dissolved in 5 mL of TFA, stirred atroom temperature for 2 h. Then the reaction mixture was dripped into 200mL of water to give a white precipitate. Filtration gave 0.95 g of abrownish solid which was used for next step without furtherpurification.

To a mixture of the above compound (100 mg, 0.065 mmol, 1.0 eq), anddecanal (26 μL, 0.13 mmol, 2.0 eq) in DMF (1 mL) was added DIPEA (34 μL,0.20 mmol, 3.0 eq). The reaction was stirred at ambient temperature for1 h. Then methanol (1 mL) and NaCNBH₃ (9 mg, 0.13 mmol, 2.0 eq) wasadded to the solution, followed by TFA (20 μL, 0.26 mmol, 4.0 eq).Stirring was continued for 1 h at room temperature. After the reactionwas completed, the reaction mixture was precipitated in acetonitrile.Filtration gave a white crystalline solid which was used for next stepwithout further purification.

The above compound was dissolved in 3 mL on DMF, addition of 0.5 mL ofpiperidine gave a light brownish solution. After stirring at ambienttemperature for 2 h, reaction mixture was triturated in acetonitrile togive a white solid, a reverse-phase HPLC purification gave the titlecompound. MS (M+H) calculated: 1342.3; observed: 1342.8.

Using the above procedures and the appropriated starting materials thecompounds shown in Tables I-VI were prepared. The mass spectral data forthese compounds were as follows:

Compound No. MW (free base) Observed MH⁺ 1 1632.6 1632.7 2 1772.9 1774.53 1604.6 1605.6 4 1576.5 1577.5 5 1582.5 1583.4 6 1658.6 1659.3 7 1693.01693.1 8 1618.6 1619.2 9 1588.5 1589.1 10 1632.6 1634.0 11 1632.6 1633.112 1632.6 1634.0 13 1646.6 1647.2 14 1630.6 1631.6 15 1628.6 1626.9 16 —— 17 1630.6 1631.9 18 — — 19 1716.8 1718.2 20 1857.0 1859.2 (M + 2H) 211793.8 1794.9 22 1747.7 1747.4 23 1854.2 1854.0 24 1779.7 1780.5 251789.7 1789.0 26 — — 27 1763.7 1764.6 28 1646.6 1646.0 29 1646.6 1646.430 1647.6 1646.7 31 1647.6 1646.6 32 1646.6 1645.5 33 1619.5 1618.5 341668.6 1667.4 35 1669.6 1669.2 36 1649.7 1648.7 37 1618.5 1619.9 381632.6 1631.9 39 1660.6 1661.6 40 1604.5 1605.5 41 1618.5 1619.9 421632.6 1633.7 43 1758.8 1760.1 44 — — 45 — — 46 — — 47 — — 48 — — 49 — —50 — — 51 1739.8 1739.4 52 — — 53 — — 54 1675.7 1676.6 55 — — 56 — — 57— — 58 1719.7 1720.5 59 — — 60 — — 61 1689.7 1690.7 62 — — 63 1703.71705.2 64 — — 65 — — 66 — — 67 — — 68 — — 69 — — 70 — — 71 — — 72 — — 73— — 74 — — 75 — — 76 — — 77 — — 78 1582.5 1583.4 79 — — 80 — — 81 — — 82— — 83 — — 84 1624.5 1625.9 85 1638.6 1639.4 86 1652.6 1654.1 87 1674.61676.0 88 — — 89 1674.6 1676.0 90 — — 91 — — 92 — — 93 — — 94 — — 951632.6 1633.7 96 1632.6 1634.0 97 1646.6 1646.9 98 1660.7 1661.9 991674.7 1675.7 100 1604.6 1605.6 101 1588.5 1589.1 102 1621.6 1620.6 1031619.5 1619.1 104 1696.7 1695.8 105 1697.7 1696.9 106 1628.6 1627.2 1071614.6 1615.2 108 1586.5 1587.2 109 1614.6 1615.2 110 1616.9 1617.8 1111688.6 1689.8 112 1702.6 1703.9 113 1723.0 1723.8 114 1640.5 1641.8 1151668.6 1669.4 116 1696.7 1697.6 117 1724.7 1726.2 118 1638.6 1640.0 1191690.6 1690.6 120 1726.6 1728.3 121 1744.7 1745.7 122 1652.6 1653.2 1231680.7 1682.9 124 1690.6 1691.3 125 1810.8 1811.0 126 1712.7 1713.4 1271687.7 1688.3 128 1719.7 1719.2 129 1546.4 1547.1 130 1619.5 1618.5 1311761.7 1761.2 132 1818.8 1819.2 133 1572.5 1571.1 134 1832.8 1831.3 1351832.8 1833.0 136 1761.7 1761.3 137 1718.7 1719.9 138 1708.6 1709.1 139— — 140 1917.9 1916.8 141 1703.7 1704.8 142 1807.8 1809.1 143 1775.81776.9 144 1873.7 1875.1 145 1809.8 1810.8 146 1703.7 1703.9 147 1674.61675.7 148 1665.7 1665.8 149 1653.7 1654.7 150 1690.6 1691.9 151 1731.71732.8 152 1743.0 1743.6 153 1704.7 1703.6 154 1809.8 1810.8 155 1759.81761.0 156 1535.4 1536.7 157 1637.6 1637.3 158 1743.0 1743.6 159 1696.71696.4 160 1757.1 1757.5 161 1884.2 1885.0 162 1838.1 1838.7 163 1758.71759.8 164 1660.7 1661.5 165 1760.8 1761.6 166 1857.8 1858.6 167 1783.81785.0 168 1887.7 1888.3 169 1813.7 1814.3 170 1776.6 1777.5 171 1738.61739.7 172 1654.6 1655.6 173 1670.6 1671.5 174 1624.5 1625.6 175 1662.61664.0 176 1640.5 1641.5 177 1682.6 1683.8 178 1638.6 1639.7 179 1688.61689.5 180 1684.6 1685.9 181 1624.5 1625.9 182 1736.7 1737.6 183 1721.71721.7 184 1783.8 1783.0 185 1883.9 1885.0 186 1878.8 1879.1 187 1716.71717.0 188 1800.8 1801.0 189 1802.9 1804.4 190 1792.8 1794.2 191 1840.91841.9 192 1766.7 1768.8 193 1807.8 1808.8 194 1780.8 1781.8 195 1765.81766.9 196 1808.8 1809.1 197 1775.8 1776.8 198 1829.8 1830.8 199 1809.81810.9 200 1844.9 1847.2 201 1778.8 1781.5 202 1803.9 1806.9 203 1786.81789.8 204 1729.7 1732.2 205 1796.8 1799.5 206 1750.7 1754.8 207 1892.91896.5 208 1851.9 1855.9 209 1865.9 1869.2 210 1841.9 1846.2 (M + 2H)211 1717.7 1718.7 212 1729.7 1731.0 213 1729.7 1731.0 214 1760.8 1761.0215 1795.8 1796.4 216 1703.7 1705.1 217 1761.7 1763.4 218 1830.8 1830.9219 1731.7 1733.1 220 1775.8 1777.5 221 1760.8 1761.9 222 1743.7 1744.8223 2098.1 2085   (M + 2H) 224 2020.1 2022.2 (M + 2H) 225 1743.0 1743.7226 1764.7 1765.6 227 1784.7 1784.8 228 1740.6 1740.8 229 1697.7 1698.5230 1647.6 1648.7 231 1855.5 1856.8 232 1655.6 1656.5 233 1677.7 1679.0234 1635.6 1636.7 235 1811.8 1812.6 236 1711.7 1712.7 237 1649.7 1649.5238 1663.7 1663.5 239 1683.7 1684.4 240 1649.7 1650.7 241 1669.7 1669.9242 1725.8 1726.6 243 1669.7 1670.6 244 1661.7 1661.7 245 1774.5 1774.6246 1788.6 1788.7 247 1726.1 1726.6 248 1740.1 1741.0 249 1663.7 1664.5250 1667.7 1678.9 251 1699.7 1700.5 252 1659.7 1660.3 253 1740.1 1740.7254 1754.1 1754.5 255 1699.6 1700.5 256 1810.8 1810.9 257 1757.6 1759.6258 1716.7 1717.6 259 1786.7 1786.4 260 1665.7 1665.8 261 1699.7 1699.7262 1713.7 1714.6 263 1722.1 1722.9 264 1736.2 1736.8 265 1681.7 1680.8266 1826.8 1826.1 267 1706.7 1706.0 268 1675.7 1674.2 269 1718.7 1718.6270 1690.6 1691.3 271 1748.7 1749.2 272 1723.7 1722.2 273 1810.8 1811.0274 1774.7 — 275 1766.7 1768.0 276 1889.0 1898.8 277 1718.7 1719.1 2781840.8 1842.0 279 1830.8 1830.9 280 1846.0 1846.8 281 1674.6 1675.7 2821839.8 1840.4 283 1900.2 1900.4 284 1855.8 1857.1 285 2001.0 2001.6 2861954.9 1954.5 287 1661.7 1662.7 288 1857.2 1857.2 289 1719.6 1720.4 2901801.9 1803.0 291 1733.7 1735.8 292 1775.8 1776.6 293 1731.7 1732.8 2941749.8 1750.8 295 1735.7 1736.7 296 1749.8 1750.5 297 1746.8 1747.8 2981832.0 1832.7 299 1769.8 1771.2 300 1788.8 1790.1 301 1774.8 1776.3 3021875.8 1874.7 303 1903.9 1901.9 304 1954.9 1954.5 305 1855.8 1857.1 3061855.8 1857.1 307 1915.8 — 308 2047.1 2048.6 (M + 2H) 309 1811.8 1813.2310 1861.0 1861.9 311 1856.9 1856.6 312 1839.8 1840.8 313 1633.6 1634.8314 1777.7 1779.0 315 1697.7 1698.7 316 1725.7 1726.6 317 1753.8 1754.8318 1689.7 1690.9 319 1872.9 1872.8 320 1950.3 1951.1 321 1835.8 1836.9322 1813.8 1813.6 323 1964.3 1964.9 324 1845.8 1846.8 325 1755.7 1757.1326 1930.3 1931.5 327 1894.9 1896.1 328 1766.8 1766.3 329 1864.8 1866.1330 1867.9 1868.6 331 1857.7 1858.9 332 1947.8 1948.9 333 1877.8 1878.7334 1809.8 1811.1 335 1825.8 1827.1 336 1833.9 1834.8 337 1914.9 1915.3338 1650.6 1651.6 339 1664.7 1665.7 340 1739.7 1740.7 341 1678.7 1679.2342 1711.7 1712.2 343 1933.8 1935.2 344 1706.8 1707.7 345 1767.8 1768.6346 1698.7 1699.0 347 1726.7 1727.8 348 1754.8 1755.4 349 1772.7 1773.4350 1904.9 1905.8 351 1738.8 1739.8 352 1856.9 1856.6 353 1505.4 1506.1354 1505.4 1506.7 355 1688.8 1689.8 356 1712.7 1713.9 357 1666.6 1668.7358 1589.6 1590.8 359 1603.6 1604.6 360 1633.6 1635.1 361 1633.6 1634.3362 1634.5 1635.5 363 1547.5 1548.1 364 1642.6 1643.6 365 1620.5 1621.7366 1618.6 1620.0 367 1604.6 1605.5 368 1588.6 1590.8 369 1652.6 1653.5370 1576.5 1576.7 371 1668.6 1669.7 372 1668.6 1669.7 373 1756.7 1758.2374 1751.6 1753.0 375 1589.5 1590.5 376 1673.6 1674.8 377 1675.7 1676.1378 1641.5 1642.0 379 1640.5 1640.7 380 1665.6 1666.8 381 1713.7 1714.2382 1639.6 1641.0 383 1680.6 1682.0 384 1653.6 1654.7 385 1638.6 1638.9386 1681.6 1683.5 387 1650.5 1651.9 388 1688.6 1704.0 389 1657.7 1659.0390 1648.6 1650.0 391 1656.5 1657.8 392 1710.6 1711.4 393 1682.6 1683.5394 1719.6 1720.7 395 1699.5 1698.7 396 1653.5 1654.7 397 1678.6 1679.8398 1661.6 1661.8 399 1604.5 1605.4 400 1671.6 1672.0 401 1604.6 1605.7402 1695.7 1696.7 403 1562.5 1562.9 404 1632.6 1634.0 405 1618.6 1619.9406 1709.7 1710.7 407 1737.7 1738.9 408 1765.8 1766.8 409 1662.7 1663.5410 1676.7 1676.8 411 1751.8 1753.0 412 1690.7 1691.2 413 1723.7 1723.9414 1718.8 1719.7 415 1710.7 1711.6 416 1738.8 1738.9 417 1766.8 1767.4418 1784.7 1784.4 419 1313.3 1314.6 420 1256.4 1257.7 421 1631.6 1632.2422 1342.3 1342.8

Example 11 Determination of Antibacterial Activity

A. In Vitro Determination of Antibacterial Activity

1. Determination of Minimal Inhibitory Concentrations (MICs)

Bacterial strains were obtained from either American Type Tissue CultureCollection (ATCC), Stanford University Hospital (SU), Kaiser PermanenteRegional Laboratory in Berkeley (KPB), Massachusetts General Hospital(MGH), the Centers for Disease Control (CDC), the San FranciscoVeterans' Administration Hospital (SFVA) or the University of CaliforniaSan Francisco Hospital (UCSF). Vancomycin resistant enterococci werephenotyped as Van A or Van B based on their sensitivity to teicoplanin.Some vancomycin resistant enterococci that had been genotyped as Van A,Van B, Van C1 or Van C2 were obtained from the Mayo Clinic.

Minimal inhibitory concentrations (MICs) were measured in amicrodilution broth procedure under NCCLS guidelines. Routinely, thecompounds were serially diluted into Mueller-Hinton broth in 96-wellmicrotiter plates. Overnight cultures of bacterial strains were dilutedbased on absorbance at 600 nm so that the final concentration in eachwell was 5×10⁵ cfu/mL. Plates were returned to a 35° C. incubator. Thefollowing day (or 24 hours in the case of Enterococci strains), MICswere determined by visual inspection of the plates. Strains routinelytested in the initial screen included methicillin-sensitiveStaphylococcus aureus (MSSA), methicillin-resistant Staphylococcusaureus, methicillin-sensistive Staphylococcus epidermidis (MSSE),methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycinsensitive Enterococcus faecium (VSE Fm), vancomycin sensitiveEnterococcus faecalis (VSE Fs), vancomycin resistant Enterococcusfaecium also resistant to teicoplanin (VRE Fm Van A), vancomycinresistant Enterococcus faecium sensistive to teicoplanin (VRE Fm Van B),vancomycin resistant Enterococcus faecalis also resistant to teicoplanin(VRE Fs Van A), vancomycin resistant Enterococcus faecalis sensitive toteicoplanin (VRE Fs Van B), enterococcus gallinarium of the Van Agenotype (VRE Gm Van A ), enterococcus gallinarium of the Van C-1genotype (VRE Gm Van C-1), enterococcus casseliflavus of the Van C-2genotype (VRE Cs Van C-2), enterococcus flavescens of the Van C-2genotype (VRE Fv Van C-2), and penicillin-sensitive Streptococcuspneumoniae (PSSP) and penicillin-resistant Streptococcus pneumoniae(PSRP). Because of the inability of PSSP and PSRP to grow well inMueller-Hinton broth, MICs with those strains were determined usingeither TSA broth supplemented with defibrinated blood or blood agarplates. Compounds which had significant activity against the strainsmentioned above were then tested for MIC values in a larger panel ofclinical isolates including the species listed above as well asnon-speciated coagulase negative Staphylococcus both sensitive andresistant to methicillin (MS-CNS and MR-CNS). In addition, they weretested for MICs against gram negative organisms, such as Escherichiacoli and Pseudomonas aeruginosa.

2. Determination of Kill Time

Experiments to determine the time required to kill the bacteria wereconducted as described in Lorian, “Antibiotics in Laboratory Medicine”,Fourth Edition, Williams and Wilkins (1991), the disclosure of which isincorporated herein by reference in its entirety. These experiments wereconducted normally with both staphylococcus and enterococcus strains.

Briefly, several colonies were selected from an agar plate and grown at35° C. under constant agitation until it achieved a turbidity ofapproximately 1.5 and 10⁸ CFU/mL. The sample was then diluted to about6×10⁶ CFU/mL and incubated at 35° C. under constant agitation wascontinued. At various times aliquots were removed and five ten-foldserial dilutions were performed. The pour plate method was used todetermine the number of colony forming units (CFUs).

The compounds of this invention were active in the above tests in vitrotests and demonstrated a broad spectrum of activity.

B. In Vivo Determination of Antibacterial Activity

1. Acute Tolerability Studies in Mice

In these studies, a compound of this invention was administered eitherintravenously or subcutaneously and observed for 5-15 minutes. If therewere no adverse effects, the dose was increased in a second group ofmice. This dose incrementation continued until mortality occurred, orthe dose was maximized. Generally, dosing began at 20 mg/kg andincreased by 20 mg/kg each time until the maximum tolerated dose (MTD)is achieved.

2. Bioavailability Studies in Mice

Mice were administered a compound of this invention either intravenouslyor subcutaneously at a therapeutic dose (in general, approximately 50mg/kg). Groups of animals were placed in metabolic cages so that urineand feces could be collected for analysis. Groups of animals (n=3) weresacrificed at various times (10 min, 1 hour and 4 hours). Blood wascollected by cardiac puncture and the following organs wereharvested—lung, liver, heart, brain, kidney, and spleen. Tissues wereweighed and prepared for HPLC analysis. HPLC analysis on the tissuehomogenates and fluids was used to determine the concentration of thetest compound or IiI present. Metabolic products resulting from changesto the test compound were also determined at this juncture.

3. Mouse Septecemia Model

In this model, an appropriately virulent strain of bacteria (mostcommonly S. aureus, or E. Faecalis or E. Faecium) was administered tomice (N=5 to 10 mice per group) intraperitoneally. The bacteria wascombined with hog gastric mucin to enhance virulence. The dose ofbacteria (normally 10⁵⁻¹⁰ ⁷) was that sufficient to induce mortality inall of the mice over a three day period. One hour after the bacteria wasadministered, a compound of this invention was administered in a singledose either IV or subcutaneously. Each dose was administered to groupsof 5 to 10 mice, at doses that typically ranged from a maximum of about20 mg/kg to a minimum of less than 1 mg/kg. A positive control (normallyvancomycin with vancomycin sensitive strains) was administered in eachexperiment. The dose at which approximately 50% of the animals are savedwas calculated from the results.

4. Neutropenic Thigh Model

In this model, antibacterial activity of a compound of this inventionwas evaluated against an appropriately virulent strain of bacteria (mostcommonly S. aureus, or E. Faecalis or E. Faecium, sensitive or resistantto vancomycin). Mice were initially rendered neutropenic byadministration of cyclophosphamide at 200 mg/kg on day 0 and day 2. Onday 4 they were infected in the left anterior thigh by an IM injectionof a single dose of bacteria. The mice were then administered the testcompound one hour after the bacteria and at various later times(normally 1, 2.5, 4 and 24 hours) the mice were sacrificed (3 per timepoint) and the thigh excised, homogenized and the number of CFUs (colonyforming units) were determined by plating. Blood was also plated todetermine the CFUs in the blood.

5. Pharmacokinetic Studies

The rate at which a compound of this invention is removed from the bloodcan be determined in either rats or mice. In rats, the test animals werecannulated in the jugular vein. The test compound was administered viatail vein injection, and at various time points (normally 5, 15, 30, 60minutes and 2, 4, 6 and 24 hours) blood was withdrawn from the cannulaIn mice, the test compound was also administered via tail veininjection, and at various time points. Blood was normally obtained bycardiac puncture. The concentration of the remaining test compound wasdetermined by HPLC.

The compounds of this invention were active in the above tests in vivotests and demonstrated a broad spectrum of activity.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula II:

wherein R¹⁶ is hydrogen or methyl; R²⁶ is hydrogen or methyl; R²⁷ ishydrogen or —CH₂COOH; R^(a) is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—;R^(b) is alkylene having from 8 to 12 carbon atoms; and pharmaceuticallyacceptable salts, stereoisomers and prodrugs thereof.
 2. The compound ofclaim 1, wherein R¹⁶ is methyl.
 3. The compound of claim 1, wherein R²⁶is methyl.
 4. The compound of claim 1, wherein R²⁷ is hydrogen.
 5. Thecompound of claim 1, wherein R^(a) is —CH₂CH₂—.
 6. The compound of claim1, wherein —R^(b)—H is an n-octyl, n-nonyl, n-decyl, n-undecyl orn-dodecyl group.
 7. The compound of claim 1, wherein —R^(b)—H is ann-decyl group.
 8. The compound of claim 1, wherein R¹⁵ is—CH₂CH₂—NH—(CH₂)₁₀—H.
 9. A pharmaceutical composition comprising acompound of any of claims 1-8 and a pharmaceutically acceptable carrier.10. A method of inhibiting the growth of bacteria in a mammal infectedwith or exposed to bacteria, the method comprising administering to themammal a composition according to claim 9 for a time and underconditions effective to inhibit growth of bacteria.